Carbamoyloxy derivatives of mutiline and their use as antibacterials

ABSTRACT

Derivatives of mutiline of formula (1A) and pharmaceutically acceptable salts and derivatives thereof, in which R 1  is ethyl or vinyl, Y is a carbamoyloxy group, in which the N-atom is unsubstituted, or mono- or di-substituted, are useful in the treatment of bacterial infections. ##STR1##

The present invention relates to novel compounds, to processes for theirpreparation, to pharmaceutical compositions containing them and to theiruse in medical therapy, particularly antibacterial therapy.

Pleuromutilin, the compound of formula (1), is a naturally occurringantibiotic which has antimycoplasmal activity and modest antibacterialactivity. It has been shown that the antimicrobial activity can beimproved by replacing the glycolic ester moiety at position 14 by anR--X--CH₂ CO₂ -- group, where R is an aliphatic or aromatic moiety and Xis O, S, or NR' (H Egger and H Reinshagen, J Antibiotics, 1976, 29,923). Tiamulin, the compound of formula (2), which is used as aveterinary antibiotic, is a derivative of this type (G Hogenauer inAntibiotics, Vol. V, part 1, ed. F E Hahn, Springer-Verlag, 1979,p.344). ##STR2##

In this application, the non-conventional numbering system which isgenerally used in the literature (G Hogenauer, loc.cit.) is used.

We have found that pleuromutilin analogues containing a 14-O-carbamoylgroup, also have improved antimicrobial properties.

Accordingly, in its broadest aspect, the present invention provides a14-O-carbamoyl derivative of mutilin or 19,20-dihydromutilin, in whichthe N-atom of the carbamoyl group is unsubstituted, mono- ordi-substituted.

More specifically, this invention provides a compound of general formula(3) ##STR3## in which: R¹ is vinyl or ethyl;

R² and R³ are the same or different groups selected from

hydrogen;

a straight or branch chained, saturated or unsaturated, optionallysubstituted, C₁ to C₆ hydrocarbon group;

a saturated or unsaturated, optionally substituted, C₃ to C₈ cyclichydrocarbon group;

an optionally substituted heterocyclic group;

an optionally substituted aryl group;

or together form an optionally substituted cyclic group of 3 to 8 ringatoms, optionally containing one additional heteroatom selected from N,O and S, and optionally fused to a hydrocarbon ring, a heterocyclicgroup or an aromatic group; or

R² is one of the above monovalent groups and R³ is a group selected fromSO₂ R⁴, COR⁵, OR⁵ and NR⁶ R⁷ where

R⁴ is selected from a straight or branch chained, saturated orunsaturated, optionally substituted, C₁ to C₆ hydrocarbon group; asaturated or unsaturated, optionally substituted, C₃ to C₈ cyclichydrocarbon group; an optionally substituted heterocyclic group; anoptionally substituted aryl group; an optionally substituted C₁ to C₆alkyl amino group; and an optionally substituted aryl amino group;

R⁵ is selected from hydrogen; a straight or branch chained, saturated orunsaturated, optionally substituted, C₁ to C₆ hydrocarbon group; asaturated or unsaturated, optionally substituted, C₃ to C₈ cyclichydrocarbon group; an optionally substituted heterocyclic group; and anoptionally substituted aryl group;

R⁶ and R⁷ are the same or different groups selected from hydrogen; astraight or branch chained, saturated or unsaturated, optionallysubstituted, C₁ to C₆ hydrocarbon group; a saturated or unsaturated,optionally substituted, C₃ to C₈ cyclic hydrocarbon group; an optionallysubstituted heterocyclic group, and an optionally substituted arylgroup; or together form an optionally substituted cyclic group of 3 to 8ring atoms, optionally containing one additional heteroatom selectedfrom N, O and S, and optionally fused to a hydrocarbon ring, aheterocyclic group or an aromatic group.

Suitable C₁ to C₆ hydrocarbon groups include straight and branched chainalkyl groups having from 1 to 6 carbon atoms, for instance methyl,ethyl, n-propyl and iso-propyl, preferably methyl.

Suitable C₃ to C₈ cyclic hydrocarbon groups include cyclopropyl,cyclopentyl and cyclohexyl.

Suitable optional substituents for the (C₁₋₆)alkyl groups and the(C₃₋₈)cycloalkyl groups include, for example, halogen, hydroxy,(C₁₋₆)alkoxy, aryloxy, carboxy and salt thereof, (C₁₋₆)alkoxycarbonyl,carbamoyl, mono- or di(C₁₋₆)alkylcarbamoyl, sulphamoyl, mono- anddi(C₁₋₆)alkylsulphamoyl, amino, mono- and di(C₁₋₆)alkylamino,(C₁₋₆)acylamino, ureido, (C₁₋₆)alkoxycarbonylamino, aryl, heterocyclyl,oxo, hydroxyimino, acyl, (C₁₋₆)alkylthio, arylthio,(C₁₋₆)alkane-sulphinyl, arylsulphinyl, (C₁₋₆)alkanesulphonyl,arylsulphonyl.

When used herein, the term "aryl" includes phenyl and naphthyl. Suitablyan aryl group, including phenyl and naphthyl, may be optionallysubstituted by up to five, preferably up to three substituents. Suitablesubstituents include halogen, (C₁₋₆)alkyl, aryl(C₁₋₄)alkyl,(C₁₋₆)alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, hydroxy, nitro,amino, mono- and di-N-(C₁₋₆)alkylamino, acylamino, acyloxy, carboxy,carboxy salts, carboxy esters, carbamoyl, mono- anddi-N-(C₁₋₆)alkylcarbamoyl, (C₁₋₆)alkoxycarbonyl, aryloxycarbonyl,ureido, guanidino, sulphonylamino, aminosulphonyl, (C₁₋₆)alkylthio,(C₁₋₆)alkyl sulphinyl (C₁₋₆)alkylsulphonyl, heterocyclyl andheterocyclyl (C₁₋₄)alkyl. In addition, two adjacent ring carbon atomsmay be linked by a (C₃₋₅)alkylene chain, to form a carbocyclic ring.

When used herein, the term "heteroaryl" includes aromatic single andfused rings containing up to four heteroatoms in each ring, each ofwhich is selected from oxygen, nitrogen and sulphur, which rings may beunsubstituted or substituted by, for example, up to three substituents.Each heteroaryl ring suitably has 5 or 6 ring atoms. A fused heteroarylring may include carbocyclic rings and need include only one heteroarylring.

When used herein the terms "heterocyclyl" and "heterocyclic" suitablyinclude, unless otherwise defined, aromatic and non-aromatic, single andfused, rings suitably containing up to four heteroatoms in each ring,each of which is selected from oxygen, nitrogen and sulphur, whichrings, may be unsubstituted or substituted by, for example, up to threesubstituents. Each heterocyclic ring suitably has from 4 to 7,preferably 5 or 6, ring atoms. A fused heterocyclic ring system mayinclude carbocyclic rings and need include only one heterocyclic ring.

Preferably a substituent for a heteroaryl or a heterocyclyl group isselected from halogen, (C₁₋₆)alkyl, aryl(C₁₋₄)alkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkoxy(C₁₋₆)alkyl, halo(C₁₋₆)alkyl, hydroxy, amino, mono- anddi-N-(C₁₋₆)alkyl-amino, acylamino, carboxy salts, carboxy esters,carbamoyl, mono- and di-N-(C₁₋₆)alkylcarbonyl, aryloxycarbonyl,(C₁₋₆)alkoxycarbonyl(C₁₋₆)alkyl, aryl, oxy groups, ureido, guanidino,sulphonylamino, aminosulphonyl, (C₁₋₆)alkylthio, (C₁₋₆)alkylsulphinyl,(C₁₋₆)alkylsulphonyl, heterocyclyl and heterocyclyl(C₁₋₄)alkyl.

Particularly suitable values for R² and R³ are hydrogen, hydroxy,methoxy, phenyl, methyl, iso-propyl, phenylsulphonyl, methoxyphenyl,nitrophenyl, trichloroacetyl, benzyl, hydroxyiminobenzyl,benzylamino-sulfonyl, dichloropyridinyl, hydroxyethyl, 2-phenylethyl,1-(R)-phenyl-2-hydroxyethyl, 2-(methoxycarbonyl)ethyl, 2-carboxyethyl,dimethylamino, dimethylaminopropyl, methanesulphonylamino,methanesulphonyl, benzoylamino, benzoyl optionally substituted bytrifluoromethyl, carboxy, methoxy, hydroxy, acetoxy, amino or nitro,furoyl, nicotinoyl, isonicotinoyl, acetyl, phenylacetyl, and phenoxy.Particularly suitable values for cyclic groups R² R³ N are indolino andmorpholino.

In a further aspect the present invention provides a method forpreparing compounds of the invention, which comprises reacting acompound of formula (4) where X is hydrogen or a hydroxyl protectinggroup, such as an acyl group, or a compound of formula (5) with anappropriately substituted carbamate-forming reagent. ##STR4##

General methods for preparing carbamates are described, for example, byA F Hegarty in Comprehensive Organic Chemistry, Vol. 2, ed. I OSutherland, Pergamon Press, 1979, p.1083. Typical procedures arereaction with an isocyanate or a carbamoyl chloride, or reaction withphosgene or a phosgene equivalent followed by reaction with an amine.

More particularly, in one aspect the present invention provides aprocess for the preparation of a compound of formula (3) which comprisesreacting a compound of formula (4) in which X is hydrogen or a hydroxylprotecting group, with

(a) a compound R² NCO,

(b) a compound R² R³ NCOCl, or

(c) phosgene or a chloroformate or a carbonate followed by a compound R²R³ NH,

where R² and R³ are as defined above and are protected whereappropriate, and where necessary deprotecting the group X to generate ahydroxyl group at position 11, deprotecting a protected group R² or R³,converting one group R² or R³ to another group R² or R³, orhydrogenating the vinyl group at position 12 to form an ethyl group.

Although in principle it may be possible to prepare compounds of formula(3) by reaction at the 14-hydroxyl in the known compound mutilin (X=H informula (4)), in practice it is desirable to use an intermediate inwhich the 11-hydroxyl is protected.

Suitable compounds as formula (4) are

11-O-acyl mutilin derivatives, e.g. mutilin 11-acetate (X=Ac in formula(4)) (A J Birch, C W Holzapfel, R W Richards, Tetrahedron (Suppl.),1966, 8, Part II, 359). After formation of the 14-O-carbamoylderivative, the 11-O-acyl group may be removed by selective hydrolysis(e.g. using NaOH in MeOH);

In another aspect, the present invention provides a process for thepreparation of a compound of formula (3) which comprises reacting acompound of formula (5), with

(a) a compound R² NCO,

(b) a compound R² R³ NCOCl, or

(c) phosgene or a chloroformate or a carbonate followed by a compound R²R³ NH,

where R² and R³ are as defined above and are protected whereappropriate, treating the product with acid, deprotecting a protectedgroup R² or R³, converting one group R² or R³ to another group R² or R³,or hydrogenating the vinyl group at position 12 to form an ethyl group.

Formula (5) is

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (H Berner, G Schulzand H Schneider, Tetrahedron, 1980, 36, 1807). After formation of the14-carbamate, the intermediate may be converted into (3) by treatmentwith conc. HCl or Lukas reagent (conc. HCl saturated with ZnCl₂) indioxane.

For preparation of 19,20-dihydro analogues (compounds of formula (3) inwhich R¹ =Et), before or after the carbamoylation, of a compound offormula (4) or (5), a vinyl group R¹ can be reduced by hydrogenationover a palladium catalyst (e.g. 10% Palladium-on-carbon) in a solventsuch as ethyl acetate, ethanol, dioxane, or tetrahydrofuran.

The formation of the carbamate at position 14 may be carried out asfollows:

(1) Reaction of the 14-hydroxyl with an isocyanate (R² N═C═O) in aninert solvent (e.g. CH₂ Cl₂, CHCl₃, tetrahydrofuran, diethyl ether,dioxane), optionally in the presence of an organic or inorganic base(e.g. N,N-di-iso-propylethylamine, K₂ CO₃). This will give an R² NHCO₂-- group at position 14. Methods for preparing isocyanate are described,for example, by J March in "Advanced Organic Chemistry", 4th ed., 1992,Wiley, N.Y., p.1290.

(2) Reaction of the 14-hydroxyl with an N,N-disubstituted carbamoylchloride (R² R³ NCOCl) in the presence of a hindered tertiary base (e.g.2,6-lutidine, N,N-di-iso-propylethylamine) in an inert solvent (e.g. CH₂Cl₂, CHCl₃, tetrahydrofuran, diethyl ether, dioxane). This will give anR² R³ NCO₂ -- group at position 14. Methods for preparing carbomoylchlorides are described, for example, by A F Hegarty, loc. cit. p.1088.

(3) Reaction of the 14-hydroxyl with phosgene or an equivalent reagent[e.g. trichloromethyl chloroformate, bis(trichloromethyl) carbonate] inthe presence of an organic base (e.g. pyridine, 2,6-lutidine,N,N-di-iso-propylethylamine), and reaction of the resulting14-chloroformate with a primary or secondary amine (R² NH₂ or R² R³ NH).

Suitable hydroxy, carboxy and amino protecting groups are those wellknown in the art and which may be removed under conventional conditionsand without disrupting the remainder of the molecule. A comprehensivediscussion of the ways in which hydroxy, carboxy and amino groups may beprotected and methods for cleaving the resulting protected derivativesis given in for example "Protective Groups in Organic Chemistry" (T. W.Greene, Wiley-Interscience, New York, 2nd edition, 1991). Particularlysuitable hydroxy protecting groups include, for example, triorganosilylgroups such as, for instance, trialkylsilyl and also organocarbonyl andorganooxycarbonyl groups such as, for instance, acetyl,allyloxycarbonyl, 4-methoxybenzyloxycarbonyl and4-nitrobenzyloxycarbonyl. Particularly suitable carboxy protectinggroups include alkyl and aryl groups, for instance methyl, ethyl andphenyl. Particularly suitable amino protecting groups includealkoxycarbonyl, 4-methoxybenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl.

In cases where the intermediate of formula (4) (such as X=acetyl) isused, a base-labile protecting group may conveniently be removed at thesame time as the group X is deprotected. In cases when the intermediateof formula (5) is used, an acid-labile protecting group may convenientlybe removed at the same time as the compound (5) is converted into thecompound (3).

Intermediate compounds formed in the processes of this invention, forexample, the 14-chloroformate derivative and the 14-O-carbamoylderivatives of the compound of formula (5), are when novel also part ofthe invention.

The compounds of this invention may be in crystalline or non-crystallineform, and, if crystalline, may optionally be hydrated or solvated. Whensome of the compounds of this invention are allowed to crystallise orare recrystallised from organic solvents, solvent of crystallisation maybe present in the crystalline product. This invention includes withinits scope such solvates. Similarly, some of the compounds of thisinvention may be crystallised or recrystallised from solvents containingwater. In such cases water of hydration may be present in thecrystalline product. This invention includes within its scopestoichiometric hydrates as well as compounds containing variable amountsof water that may be produced by processes such as lyophilisation.

The compounds according to the invention are suitably provided insubstantially pure form, for example at least 50% pure, suitable atleast 60% pure, advantageously at least 75% pure, preferably at least85% pure, more preferably at least 95% pure, especially at least 98%pure, all percentages being calculated as weight/weight. An impure orless pure form of a compound according to the invention may, forexample, be used in the preparation of a more pure form of the samecompound or of a related compound (for example a correspondingderivative) suitable for pharmaceutical use.

The present invention also includes pharmaceutically acceptable saltsand derivatives of the compounds of the invention. Salt formation may bepossible when one of the substituents carries an acidic or basic group.Salts may be prepared by salt exchange in conventional manner.

The compounds of the present invention and their pharmaceuticallyacceptable salts or derivatives have antimicrobial properties and areuseful for the treatment of microbial infections in animals, especiallymammals, including humans, in particular humans and domesticated animals(including farm animals). The compounds may be used for the treatment ofinfections caused by, for example, Gram-positive and Gram-negativebacteria and mycoplasmas, including, for example, Staphylococcus aureus,Enterococcus faecalis, Streptococcus pyogenes, Streptococcus agalactiae,Streptococcus pneumoniae, Haemophilius sp., Neisseria sp., Legionellasp., Mycoplasma pneumoniae, and Mycoplasma gallisepticum.

The present invention provides a pharmaceutical composition comprising acompound of formula (3) or a pharmaceutically acceptable salt orderivative thereof together with a pharmaceutically acceptable carrieror excipient.

The present invention also provides a method of treating microbialinfections in animals, especially in humans and in domesticated mammals,which comprises administering a compound of formula (3) or apharmaceutically acceptable salt or derivative thereof, or a compositionaccording to the invention, to a patient in need thereof.

The invention further provides the use of a compound of the invention ora pharmaceutically acceptable salt or derivative thereof in thepreparation of a medicament composition for use in the treatment ofmicrobial infections.

The compounds and compositions according to the invention may beformulated for administration in any convenient way for use in human orveterinary medicine, by analogy with other antibiotics.

The compounds and compositions according to the invention may beformulated for administration by any route, for example oral, topical orparenteral. The compositions may, for example, be made up in the form oftablets, capsules, powders, granules, lozenges, creams, syrups, orliquid preparations, for example solutions or suspensions, which may beformulated for oral use or in sterile form for parenteral administrationby injection or infusion.

Tablets and capsules for oral administration may be in unit dosage form,and may contain conventional excipients including, for example, bindingagents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrollidone; fillers, for example lactose, sugar,maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; and pharmaceuticallyacceptable wetting agents, for example sodium lauryl sulphate. Thetablets may be coated according to methods well known in normalpharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or anothersuitable vehicle before use. Such liquid preparations may containconventional additives, including, for example, suspending agents, forexample sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel orhydrogenated edible fats; emulsifying agents, for example lecithin,sorbitan monooleate or acacia; non-aqueous vehicles (which may includeedible oils), for example almond oil, oily esters (for exampleglycerine), propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid; and, ifdesired, conventional flavouring and colour agents.

Compositions according to the invention intended for topicaladministration may, for example, be in the form of ointments, creams,lotions, eye ointments, eye drops, ear drops, nose drops, nasal sprays,impregnated dressings, and aerosols, and may contain appropriateconventional additives, including, for example, preservatives, solventsto assist drug penetration, and emollients in ointments and creams. Suchtopical formulations may also contain compatible conventional carriers,for example cream or ointment bases, and ethanol or oleyl alcohol forlotions. Such carriers may constitute from about 1% to about 98% byweight of the formulation; more usually they will constitute up to about80% by weight of the formulation.

Compositions according to the invention may be formulated assuppositories, which may contain conventional suppository bases, forexample cocoa-butter or other glycerides.

Compositions according to the invention intended for parenteraladministration may conveniently be in fluid unit dosage forms, which maybe prepared utilizing the compound and a sterile vehicle, water beingpreferred. The compound, depending on the vehicle and concentrationused, may be either suspended or dissolved in the vehicle. In preparingsolutions, the compound may be dissolved in water for injection andfilter-sterilised before being filled into a suitable vial or ampoule,which is then sealed. Advantageously, conventional additives including,for example, local anaesthetics, preservatives, and buffering agents canbe dissolved in the vehicle. In order to enhance the stability of thesolution, the composition may be frozen after being filled into thevial, and the water removed under vacuum; the resulting dry lyophilizedpowder may then be sealed in the vial and a accompanying vial of waterfor injection may be supplied to reconstitute the liquid prior to use.Parenteral suspensions may be prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilisation cannot be accomplished by filtration. Thecompound may instead be sterilised by exposure to ethylene oxide beforebeing suspended in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in such suspensions in order to facilitateuniform distribution of the compound.

A compound or composition according to the invention may suitably beadministered to the patient in an antimicrobially effective amount.

A composition according to the invention may suitably contain from 0.1%by weight, preferably from 10 to 60% by weight, of a compound accordingto the invention (based on the total weight of the composition),depending on the method of administration.

The compounds according to the invention may suitably be administered tothe patient at a daily dosage of from 1.0 to 50 mg/kg of body weight.For an adult human (of approximately 70 kg body weight), from 50 to 3000mg, for example about 1500 mg, of a compound according to the inventionmay be administered daily. Suitably, the dosage for adult humans is from5 to 20 mg/kg per day. Higher or lower dosages may, however, be used inaccordance with normal clinical practice.

When the compositions according to the invention are presented in unitdosage form, each unit dose may suitably comprise from 25 to 1000 mg,preferable from 50 to 500 mg, of a compound according to the invention.

The following Examples illustrate the present invention.

EXAMPLE 1 Mutilin 14-(N-phenylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-phenyl-carbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (H Berner, G Schulzand H Schneider, Tetrahedron, 1980, 36, 1807) (170 mg) in dry CH₂ Cl₂ (3ml) was treated with phenyl isocyanate (0.12 ml) andN,N-di-iso-propylethylamine (1 drop) and the solution was kept at roomtemperature, with exclusion of moisture, for 7 days. The solution wasdiluted with ethyl acetate (50 ml) and was washed with dil. HCl (20 ml),water (20 ml), and saturated NaHCO₃ solution (20 ml). The solution wasdried (Na₂ SO₄) and the solvent was removed by evaporation under reducedpressure to yield a colourless oil. The oil was chromatographed onsilica gel, using 1:4 ethyl acetate-hexane, to give(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-phenylcarbamate) as a colourless gum (190 mg); ν_(max) (CHCl₃)3435, 1724, 1695, 1603, and 1523 cm⁻¹.

Step 2. Mutilin 14-(N-phenylcarbamate)

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-phenyl-carbamate) (160 mg) in dioxane (3 ml) was treated with asaturated solution of zinc chloride in conc. HCl (1.2 ml) and thesolution was stirred at room temperature for 3.5 hours. The mixture wasdiluted with ethyl acetate (50 ml) and the solution was washed withsaturated NaCl solution (20 ml) and saturated NaHCO₃ solution (20 ml).The solution was dried (Na₂ SO₄) and the solvent was removed byevaporation under reduced pressure to yield a colourless oil. The oilwas chromatographed on silica gel, using 1:3 ethyl acetate-hexane, togive mutilin 14-(N-phenylcarbamate) as a colourless gum (145 mg);crystallisation from CH₂ Cl₂ -hexane gave colourless prisms (130 mg),m.p. 211-212° C.; λ_(max) (EtOH) 236 nm (ε19000); ν_(max) (CHCl₃) 3630,3562, 3435, 1726, 1602, and 1523 cm⁻¹ ; MS(EI) m/z 439 (M⁺).

EXAMPLE 2 Mutilin 14-(N-methylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-methylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)was reacted with methyl isocyanate (0.12 ml, 2.0 mmol) and N,N-di-iso-propyl-ethylamine (1 drop) in dichloromethane (5 ml), as forExample 1 Step 1, to afford the title compound (145 mg, 37%); ν_(max)(CH₂ Cl₂) 3459, 1711, and 1516 cm⁻¹ ; ¹ H NMR (CDCl₃) 6.79 (1H, dd, J17.5, 10.5 Hz) 5.65 (1H, d, J 9.9 Hz) 5.31 (1H, d, J 10.9 Hz) 5.01 (1H,d, 17.6 Hz) 4.55 (1H, br) 3.46 (1H, m) 3.23 (3H, s) 2.95 (1H, q, J 6.4Hz) 2.83 (3H,br d, J 4.8 Hz) 2.40 (1H, dd, J 15.3, 9.8 Hz) 2.20 (1H, m)2.02 (2H, m) 1.65 (3H,m) 1.47 (1H, m) 1.30-1.07 (4H, m) 1.20 (6H, s)0.99 (3H, d, J 6.4 Hz) 0.85 (3H, br d, J 6.9 Hz); MS(EI) m/z 391 (M⁺).

Step 2. Mutilin 14-(N-methylcarbamate)

The product of Step 1 (135 mg, 0.34 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (0.5 ml), as forExample 1 Step 2, to afford the title compound (89 mg, 69%); ν_(max)(CH₂ Cl₂) 3460, 1732, and 1714 cm⁻¹ ; ¹ H NMR (CDCl₃) 6.61 (1H, dd, J17.4, 11.0 Hz) 5.64 (1H, d, J 8.4 Hz) 5.37 (1H, br d, J 11.0 Hz) 5.21(1H, dd, J 17.4, 1.6 Hz) 4.47 (1H, br) 3.34 (1H, dd, J 11.0, 6.7 Hz)2.78 (3H, br d, J 4.8 Hz) 2.37 (1H, quintet, J 6.8 Hz) 2.21 (4H, m) 2.02(2H, m) 1.70 (4H, m) 1.42 (6H, m) 1.23 (3H, s) 0.86 (3H, d, J 7.0 Hz)0.76 (3H, d, J 6 Hz); MS(EI) m/z 377 (M⁺).

EXAMPLE 3 Mutilin 14-(N-iso-propylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-iso-propylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)was reacted with isopropyl isocyanate (0.2 ml, 2.0 mmol) and N,N-di-iso-propylethylamine (1 drop) in dichloromethane (5 ml), as forExample 1 Step 1, to afford the title compound (367 mg, 87%); ν_(max)(CH₂ Cl₂) 3435, 1700 cm⁻¹ ; ¹ H NMR (CDCl₃) 6.77 (1H, dd, J 17.5, 10.6Hz) 5.64 (1H, d, J 9.8 Hz) 5.30 (1H, d, J 10.6 Hz) 5.00 (1H, d, J 17.5Hz) 4.44 (1H, d, J 7.8 Hz) 3.83 (1H, m) 3.45 (1H, m) 3.22 (3H, s) 2.94(1H, q, J 6.4 Hz) 2.39 (1H, dd, 15.1, 9.9 Hz) 2.18 (1H, m) 2.00 (2H, m)1.65 (4H, m) 1.46 (1H, m) 1.29-1.05 (5H, m) 0.98 (3H, d, J 6.4 Hz) 0.84(3H, d, J 6.8 Hz); MS(EI) m/z 419 (M⁺).

Step 2. Mutilin 14-(N-iso-propylcarbamate)

The product of Step 1 (324 mg, 0.77 mmol) in dioxane (10 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml), as forExample 1 Step 2, to afford the title compound (102 mg, 33%); ν_(max)(CH₂ Cl₂) 3436, 1733, 1710, 1505 cm⁻¹ ; ¹ H NMR (CDCl₃) 6.60 (1H, dd, J17.4, 11.0 Hz) 5.64 (1H, d, J 8.4 Hz) 5.36 (1H, dd, J 11.0, 1.6 Hz) 5.20(1H, dd, J 17.5, 1.6 Hz) 4.36 (1H, br) 3.79 (1H, m) 3.34 (1H, dd, J11.0, 6.6 Hz) 2.38 (1H, m) 2.21 (2H, m) 2.02 (2H, m) 1.81-1.59 (4H, m)1.49-1.26 (7H, m) 1.14 (10H, m) 0.86 (3H, d, J 7.1 Hz) 0.76 (3H, br d, J5.8 Hz); MS(NH₃ DCI) m/z 406 (MH⁺).

EXAMPLE 4 Mutilin 14-(N-phenylsulphonylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-phenylsulphonylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)was reacted with benzenesulphonylisocyanate (0.27 ml, 2.0 mmol) andN,N-di-iso-propylethylamine (1 drop) in dichloromethane (5 ml), as forExample 1 Step 1, to afford the title compound (365 mg, 71%); ν_(max)(CH₂ Cl₂) 3361, 1745, 1698 1450 1354 cm⁻¹ ; ¹ H NMR (CDCl₃) 8.05 (2H, d,J 7.1 Hz) 7.68 (1H, t, J 7.3 Hz) 7.57 (2H, m) 6.42 (1H, dd, J 17.5, 10.7Hz) 5.67 (1H, d, J 10.0 Hz) 5.25 (1H, d, J 10.7 Hz) 4.96 (1H, d, J 17.5Hz) 3.37 (1H, ddd, J 11.1, 8.3, 5.1 Hz) 3.21 (3H, s) 2.77 (1H, q, J 6.4Hz) 2.32 (1H, dd, J 15.3, 10.0 Hz) 2.16 (1H, m) 1.99 (2H, m) 1.67 (1H,d, J 11.3 Hz) 1.48-1.02 (7H, m) 1.15 (3H, s) 1.10 (3H, s) 0.95 (3H, d, J6.4 Hz) 0.62 (3H, d, J 6.9 Hz); MS(EI) m/z 517 (M⁺), Found: 517.2504,C₂₂ H₃₉ NO₆ S requires 517.2498.

Step 2. Mutilin 14-(N-phenylsulphonylcarbamate)

The product of Step 1 (340 mg, 0.66 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (291 mg, 88%); mp 125-7°C.; ν_(max) (CH₂ Cl₂) 3364, 1736, 1450, 1420, 1353 cm⁻¹ ; ¹ H NMR(CDCl₃) 8.00 (2H, d, J 7.4 Hz) 7.65 (1H, t, J 7.4 Hz) 7.54 (2H, t, J 7.5Hz) 6.26 (1H, dd, J 17.4, 11.0 Hz) 5.61 (1H, d, J 8.4 Hz) 5.23 (1H, dd,J 11.0, 1.3 Hz) 5.07 (1H, dd, J 17.5, 1.3 Hz) 3.18 (1H, dd, J 10.1, 6.7Hz) 2.19 (3H, m) 1.95 (2H, m) 1.75-1.23 (8H, m) 1.33 (3H, s) 1.08 (1H,m) 1.07 (3H, s) 0.85 (3H, d, J 7.0 Hz) 0.51 (3H, d, J 6.7 Hz); MS(EI)m/z 503 (M⁺), Found: 503.2348, C₂₇ H₃₇ NO₆ S requires 503.2342.

EXAMPLE 5 Mutilin 14-(N-4-methoxyphenylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-4-methoxyphenylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 g, 2.97 mmol)in dry CH₂ Cl₂ (10 ml) was treated with 4-methoxyphenyl isocyanate (0.77ml, 5.95 mmol) and N,N-di-iso-propylethylamine (5 drops) and thesolution was kept at room temperature, with exclusion of moisture, for 8days. The solution was diluted with CH₂ Cl₂ and washed with waterfollowed by brine. The solution was dried (MgSO₄) and the solventremoved by evaporation under reduced pressure. The residue wastriturated with ethyl acetate/hexane and the resulting solid was removedby filtration before reducing the mother liquors to low volume underreduced pressure. Purification was accomplished by chromatography onsilica gel eluting with 1:4 ethyl acetate-hexane. The title compound wasisolated as a foam (1.37 g, 95%); ν_(max) (CH₂ Cl₂) 3428, 2932, 1722,1697, and 1597 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.89 (3H, d, J 6.1 Hz), 0.99 (3H,d, J 6.4 Hz), 1.20 (6H, s) superimposed on 1.07-1.29 (5H, m), 1.34-1.37(1H, m), 1.70 (1H, d, J 15.3 Hz), 1.73 (1H, d, J 11.3 Hz), 1.94-2.05(2H, m), 2.15-2.24 (1H, m), 2.46 (1H, dd, J 15.2, 10.0 Hz), 2.96 (1H, q,J 6.4 Hz), 3.23 (3H, s), 3.47 (1H, m), 3.80 (3H, s), 5.01 (1H, d, J 17.4Hz), 5.31 (1H, d, J 10.7 Hz), 5.77 (1H, d, J 9.9 Hz), 6.43 (1H, broads), 6.75 (1H, dd, J 17.5, 10.6 Hz), 6.86 (2H, d, J 8.9 Hz), 7.31 (2H,broad d); MS (ESI-ve ion) m/z 482 ((M-H)⁻).

Step 2. Mutilin 14-(N-4-methoxyphenylcarbamate)

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-4-methoxyphenylcarbamate) (483 mg, 1 mmol) in dioxane (5 ml) wastreated with a saturated solution of zinc chloride in conc. HCl (1 ml)as described in Example 1 Step 2. The title compound was isolated as acrystalline solid (400 mg, 86%); m.p. (CH₂ Cl₂ /hexane) 192-194° C.;ν_(max) (CH₂ Cl₂) 3625, 3563, 2937, 1725, 1597, and 1519 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.79 (3H, broad d), 0.87 (3H, d, J 7.0 Hz), 1.18 (6H, s),1.14-1.82 (13H, m), 2.04-2.26 (3H, m), 2.37 (1H, quint, J 6.9 Hz), 3.36(1H, dd, J 10.9, 6.7 Hz), 3.78 (3H, s), 4.81 (1H, dd, J 17.4, 1.6 Hz),5.36 (1H, dd, J 10.9, 1.4 Hz), 5.73 (1H, d, J 8.3 Hz), 6.39 (1H, broads), 6.59 (1H, dd, J 17.4, 10.9 Hz), 6.85 (2H, d, J 8.9 Hz), 7.26 (2H,broad d); MS (EI) m/z 469 (M⁺). C₂₈ H₃₉ NO₅ requires 469.2828, Found:469.2830.

EXAMPLE 6 Mutilin 14-(N-4-nitrophenylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-4-nitrophenylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 g, 2.97 mmol)and 4-nitrophenyl isocyanate (731 mg, 4.5 mmol) andN,N-di-iso-propylethylamine (5 drops) were dissolved in dry CH₂ Cl₂ (10ml), as described in Example 5 Step 1, to give the title compound (702mg); ν_(max) (CH₂ Cl₂) 3415, 2981, 1733, 1698, and 1599 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.87 (3H, d, J 6.9 Hz), 1.01 (3H, d, J 6.4 Hz), 1.21 (3H,s) and1.26 (3H,s) superimposed on 1.10-1.90 (6H, m), 1.68 (1H, d, J 15.4 Hz),1.75 (1H, d, J 11.5 Hz), 1.94-2.06 (2H, m), 2.16-2.25 (1H, m), 2.51 (1H,dd, J 15.2, 1 0.Hz), 2.94 (1H, q, J 6.3 Hz), 3.23 (3H, s), 3.47-3.49(1H, m), 5.04 (1H, d, J 17.5 Hz), 5.32 (1H, d, J 10.7 Hz), 5.82 (1H, d,J 9.9 Hz), 6.70 (1H, dd, J 17.5, 10.6 Hz), 6.93 (1H, broad s), 7.61 (2H,d, J 9.1 Hz), 8.22 (2H, d, J 9.1 Hz); MS (NH₃ DCI) m/z 499 (MH⁺), m/z516 (MNH₄ ⁺).

Step 2. Mutilin 14-(N-4-nitrophenylcarbamate)

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-4-nitrophenylcarbamate) (203 mg, 0.41 mmol) in dioxane (5 ml) wastreated with a saturated solution of zinc chloride in conc. HCl (0.5 ml)as described in Example 1 Step 2. The title compound was isolated as acrystalline solid (163 mg, 82%); m.p. (CH₂ Cl₂ /hexane) 208-210° C.;ν_(max) (CH₂ Cl₂) 3562, 3314, 2939, 1733, 1598, and 1536 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.78 (3H, d, J 6.5 Hz), 0.92 (3H, d, J 7.0 Hz), 1.20 (3H, s) and1.46 (3H, s) both superimposed on 1.20-1.84 (10H, m), 2.09-2.28 (3H, m),2.39 (1H, quint, J 7.0 Hz), 3.38 (1H, dd, J 10.7, 6.6 Hz), 5.23 (1H, dd,J 17.5, 1.4 Hz), 5.39 (1H, dd, J 10.9, 1.4 Hz), 5.80 (1H, d, J 9.3 Hz),6.56 (1H, dd, J 17.4, 10.9 Hz), 6.88 (1H, broad s), 7.56 (2H, d, J 9.2Hz), 8.20 (2H, d, J 9.2 Hz); MS (EI) m/z 484 (M⁺). C₂₇ H₃₆ N₂ O₆requires 484.2573, Found: 484.2571.

EXAMPLE 7 Mutilin 14-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-trichloroacetylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 g, 2.97 mmol)and trichloroacetyl isocyanate (0.389 ml, 3.3 mmol) andN,N-di-iso-propylethylamine (5 drops) were dissolved in dry CH₂ Cl₂ (10ml), as described in Example 5 Step 1, to give the title compound (1.80g, quant.); ν_(max) (CH₂ Cl₂) 3510, 3396, 1737, 1698, and 1583 cm⁻¹ ; ¹H NMR (d₆ -acetone) 0.85-0.91 (3H, m), 1.02 (3H, d, J 6.4 Hz), 1.11-1.79(14H, m), 1.90-2.23 (3H, m),2.42-2.63 (1H, m), 3.01 (1H, q, J 6.4 Hz),3.18-3.27 (5H, m), 3.50-3.59 (1H, m), 4.04-4.18 (2H, m), 4.99 (1H, d, J17.6 Hz), 5.30 (1H, d, J 10.8 Hz), 5.83-5.87 (1H, m), 6.82-6.99 (m),7.16-7.23 (m), 7.88-7.91 (m) (total 4H); MS (NH₃ DCI) m/z 521 (MH⁺), m/z539 (MNH₄ ⁺).

Step 2. Mutilin 14-(N-trichloroacetylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-trichloroacetylcarbamate) (1.8 g, 2.97 mmol) in dioxane (10 ml)was treated with a saturated solution of zinc chloride in conc. HCl (2.0ml) as described in Example 1 Step 2. The title compound was isolated asa solid (901 mg, 60%); ν_(max) (CH₂ Cl₂) 3406, 1803, and 1736 cm⁻¹ ; ¹ HNMR (d₆ -acetone) 0.89 (3H, d, J 6.8 Hz), 1.01 (3H, d, J 6.4 Hz),1.11-2.22 (17H, m), 2.55 (1H, dd, J 15.4, 10.1 Hz), 2.91-2.96 (1H, m),3.19 (3H, s), 3.45-3.55 (1H, m), 5.00 (1H, d, J 17.6 Hz), 5.31 (1H, d, J10.7 Hz), 5.88 (1H, d, 10.0 Hz), 6.74 (1H, dd, J 17.5, 10.7 Hz), 10,59(1H broad s); MS (ESI-ve ion) m/z 506 ((M-H)⁻).

Step 3. Mutilin 14-carbamate

Mutilin 14-(N-trichloroacetylcarbamate) (300 mg) was dissolved in CH₂Cl₂ (2 ml) and methanol (2 ml) before treating with potassium carbonate(122 mg, 0.9 mmol). The reaction was stirred at room temperature for 4hours before diluting with CH₂ Cl₂. The organic phase was washed withwater (twice) followed by saturated sodium chloride solution, and thesolvent removed under reduced pressure. Trituration of the residue gavethe title compound as a white solid (179 mg, 85%); ν_(max) (CH₂ Cl₂)3538, 3421, 1725, and 1582 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.79 (3H, d, J 6.4Hz), 0.86 (3H, d, J 7.0 Hz), 1.17 (3H, s), 1.39 (3H, s) superimposed on1.38-1.79 (10H, m), 2.02-2.25 (1H, d, J 8.6 Hz), 2.09 (1H, broad s),2.17-2.31 (2H,m), 2.36 (1H, quint, J 6.9 Hz), 3.35 (1H, broad t), 4.52(2H, broad s), 5.21 (1H, dd, J 17.4, 1.5 Hz), 5.36 (1H, dd, J 11.0, 1.5Hz), 5.62 (1H, d, J 8.5 Hz) 6.57 (1H, dd, J 17.4, 10.9 Hz); MS (NH₃ DCI)m/z 364 (MH⁺), m/z 381 (MNH₄ ⁺).

EXAMPLE 8 Mutilin 14-(N-benzylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-1-oxo-4-epi-mutilin14-(N-benzylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (336 mg, 1.0 mmol)was dissolved in dry CH₂ Cl₂ (5 ml) and treated with benzyl isocyanate(0.16 ml, 1.30 mmol) and N,N-di-iso-propylethylamine (5 drops) and thereaction was carried out as described in Example 5, Step 1. The titlecompound was isolated as a white foam (432 mg, 95%); ν_(max) (CH₂ Cl₂)3444, 2930, 1711, 1698, and 1456 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.87 (3H, d, J6.8 Hz), 0.98 (3H, d, J 6.4 Hz), 1.18 (3H, s) and 1.19 (3H, s) bothsuperimposed on 1.02-1.54 (6H, m), 1.67 (1H, d, J 15.2 Hz), 1.70 (1H, d,J 11.3 Hz), 1.93-2.04 (2H, m), 2.15-2.23 (1H, m), 2.42 (1H, dd, J 15.1,10.0 Hz), 2.95 (1H, q, J 6.4 Hz), 3.22 (3H, s), 3.42-3.51 (1H, m), 4.32(1H, dd, J 14.9, 5.5 Hz), 4.52 (1H, dd, J 14.9, 6.4 Hz), 4.95 (1H, broads), 5.01 (1H, d, J 17.6 Hz), 5.32 (1H, d, J 10.7 Hz), 5.69 (1H, d, J 9.8Hz), 6.79 (1H, dd, J 17.5, 10.6 Hz), 7.26-7.37 (5H, m).

Step 2. Mutilin 14-(N-benzylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-benzylcarbamate) (400 mg, 0.85 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1.0 ml) asdescribed in Example 1 Step 2. The title compound was isolated as a foam(329 mg, 82%); ν_(max) (CH₂ Cl₂) 3626, 3563, 2934, 1718, 1581, and 1510cm⁻¹ ; ¹ H NMR (CDCl₃) 0.77 (3H, d, J 5.9 Hz), 0.86 (3H, d, J 7.0 Hz),1.17 (3H, s) and 1.39 (1H, s) superimposed on 1.08-1.80 (8H, m),1.99-2.07 (3H, m), 2.17-2.24 (2H, m), 2.39 (1H, quint., J 6.9 Hz), 3.35(1H, dd, J 10.8, 6.7 Hz), 4.31 (1H, dd, J 5.9 Hz), 4.41 (1H, dd, J 16.0,6.2 Hz), 4.90 (1H, broad t), 5.20 (1H, d, J 17.3 Hz), 5.36 (1H, d, J10.9 Hz), 5.69 (1H, d, J 8.4 Hz), 6.61 (1H, dd, J 17.4, 11.0 Hz),7.24-7.43 (5H, m); MS (EI) m/z 391 (M⁺); MS (NH₃ DCI) m/z 392 (MH⁺).

EXAMPLE 9 Mutilin 14-[N-(Benzylaminosulfonyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(chlorosulfonyl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 g, 2.97 mmol)was dissolved in dry CH₂ Cl₂ (5 ml) and treated with chlorosulfonylisocyanate (0.284 ml, 3.30 mmol) and the reaction was carried out asdescribed in Example 5, Step 1. The title compound was isolated as awhite foam (1.03 g, 75%); ν_(max) (CH₂ Cl₂) 3331, 2929, 1765, 1698, and1441 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.93 (3H, d, J 6.9 Hz), 1.02 (3H, d, J 6.4Hz), 1.20 (3H, s) and 1.26.(3H, s) and 1.82 (1H, d, J 15.2 Hz) allsuperimposed on 1.22-2.26 (5H, m), 2.60 (1H, dd, J 15.4, 10.2 Hz), 2.95(1H, q, J 6.4 Hz), 2.97 (3H, s), 3.46-3.55 (1H, m), 5.02 (1H, d, J 17.5Hz), 5.33 (1H, d, J 10.7 Hz), 5.88 (1H, d, J 10.1 Hz), 6.68 (1H, dd, J17.5, 10.7 Hz).

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(benzylaminosulfonyl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(chlorosulfonyl)carbamate] (300 mg, 0.65 mmol) was dissolved indry dichloromethane under an atmosphere of argon. The solution wastreated with benzylamine (0.077 ml, 0.71 mmol) followed by triethylamine(0.1 ml, 0.71 mmol). After 12 hours stirring at room temperature thereaction was diluted with dichloromethane and washed with water andsaturated sodium chloride solution. After drying (MgSO₄) the crudematerial was purified by chromatography on silica gel eluting with 1:4ethyl acetate-hexane. The title compound was isolated as a foam (233 mg,65%); ν_(max) (CH₂ Cl₂) 3370, 2981, 2930, 1734, 1698, and 1456 cm⁻¹ ; ¹H NMR (CDCl₃) 0.88 (3H, d, J 6.8 Hz), 0.99 (3H, d, J 6.4 Hz), 1.19 (3H,s), 1.21 (3H, s), 1.54 (1H, d, J 15.4 Hz), 1.72 (1H, d, J 11.3 Hz),1.07-1.74 (6H, m), 1.93-2.02 (2H, m), 2.14 2.23 (1H, m), 2.44 (1H, dd, J15.2, 10.2 Hz), 2.84 (1H, q, J 6.5 Hz), 3.21 (3H, s), 3.38-3.47 (1H, m),4.19 (1H, dd, J 13.6, 5.3 Hz), 4.30 (1H, dd, J 13.7, 6.9 Hz), 5.02 (1H,d, J 17.5 Hz), 5.30 (1H, d, J 10.7 Hz), 5.40 (1H, broad t, J˜5.7 Hz)5.74 (1H, d, J 10.0 Hz), 6.56 (1H, dd, J 17.5, 10.7 Hz), 7.35 (5H, broads), 7.50 (1H, broad s); MS (NH₃ DCI) m/z 564 (MNH₄ ⁺); MS (EI) m/z 546(M⁺). C₂₉ H₄₂ N₂ O₆ S requires 546.2764, Found: 546.2764.

Step 3: Mutilin 14-[N-(Benzylaminosulfonyl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(benzylaminosulfonyl)carbamate] (233 mg, 0.43 mmol) in dioxane (4ml) was treated with a saturated solution of zinc chloride in conc. HCl(0.5 ml) as described in Example 1 Step 2. The title compound wasisolated as a foam (169 mg, 82%); ν_(max) (CH₂ Cl₂) 3562, 3372, 2934,and 1734 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.79 (3H, d, J 6.8 Hz), 0.88 (3H, d, J7.0 Hz), 1.20 (3H, s), 1.40 (1H, s), 1.47 (1H, d, J 10.7 Hz), 1.10-1.81(10H, m), 2.08-2.32 (5H, m), 3.36 (1H, dd, J 10.3, 6.7 Hz), 4,19 (1H,s), 4.20 (1H, s), 5.26 (1H, dd, J 17.3, 1.4 Hz), 5.37 (1H, dd, J 10.9,1.3 Hz), 5.34-5.39 (1H, m), 5.72 (1H, d, J 8.5 Hz), 6.46 (1H, dd, J17.4, 11.0 Hz), 7.28-7.37 (5H, m); MS (NH₃ DCI) m/z 550 (MNH₄ ⁺).

EXAMPLE 10 Mutilin 14-[N-(2,6-Dichloropyridin-4-yl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2,6-dichloropyridin-4-yl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (336 mg, 1.0 mmol)was dissolved in dry CH₂ Cl₂ (5 ml) and treated with2,6-dichloropyridine-4-isocyanate (283 mg, 1.5 mmol) andN,N-di-iso-propylethylamine (5 drops) and the reaction was carried outas described in Example 5, Step 1. The title compound was isolated as awhite foam (589 mg, quant.); ν_(max) (CH₂ Cl₂) 3407, 3295, 2981, 1734,1698, 1575 and 1502 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.83 (3H, d, J 6.9 Hz), 1.01(3H, d, J 6.4 Hz), 1.20 (3H, s), 1.21 (3H, s), 1.08-1.56 (6H, m) 1.64(1H, d, J 15.3 Hz), 1.74 (1H, d, J 11.3 Hz), 1.94-2.05 (2H, m),2.16-2.30 (1H, m), 2.50 (1H, dd, J 12.7, 6.4 Hz), 2.91 (1H, q, J 6.2Hz), 3.23 (3H, s), 3.41-3.48 (1H, m), 5.04 (1H, d, J 17.5 Hz), 5.36 (1H,d, J 10.7 Hz), 5.80 (1H, d, J 9.9 Hz), 6.65 (1H, dd, J 17.6, 10.7 Hz),7.07 (1H, broad s), 7.34 (1H, s), 7.44 (1H, s); MS (NH₃ DCI) m/z 523(MH⁺).

Step 2. Mutilin 14-[N-(2,6-Dichloropyridin-4-yl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2,6-dichloropyridin-4-yl)carbamate] (569 mg, 1.0 mmol) in dioxane(5 ml) was treated with a saturated solution of zinc chloride in conc.HCl (1.5 ml) as described in Example 1 Step 2. The title compound wasisolated as a foam which was crystallised from ethyl acetate/hexane (266mg, 52%), m.p. (EtOAc/hexane) 237° C.; ν_(max) (CH₂ Cl₂) 3404, 2926,1739, 1719, 1579, and 1507 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.61 (3H, d, J 6.2Hz), 0.77 (3H, d, J 7.0 Hz), 0.96-1.08 (4H, m), 0.96-1.08 (10H, m),1.90-2.27 (6H, m), 3.20-3.26 (2H, m), 5.07 (1H, dd, J 17.4, 1.4 Hz),5.22 (1H, dd, J 10.9, 1.3 Hz), 5.58 (1H, d, J 8.3 Hz), 6.34 (1H, dd, J17.4, 11.0 Hz), 7.34 (2H, s); MS (EI) m/z 508 (M⁺); MS (NH₃ DCI) m/z 509(MH⁺).

EXAMPLE 11 Mutilin-14-(N,N-Dimethylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N,N-dimethylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (336 mg, 1.0 mmol)was dissolved in pyridine (10 ml) before treating withN,N-dimethylcarbamoyl chloride (0.12 ml, 1.3 mmol). The reaction waswarmed to reflux under an atmosphere of argon. Further portions ofN,N-dimethylcarbamoyl chloride (0.12 ml, 1.3 mmol) were added to thereaction at 5 daily intervals during its duration. After 14 days atreflux the reaction was allowed to cool and then partitioned betweenethyl acetate and 1.0M HCl. The organic phase was separated and washedwith water followed by saturated sodium chloride solution. After drying(MgSO₄) the crude material was purified by chromatography on silica gel,loading in PhCH₃ and eluting with 1:9 ethyl acetate-hexane. The titlecompound was isolated as a white solid (158 mg, 40%); ν_(max) (CH₂ Cl₂)2931, 1693, and 1456 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.87 (3H, d, J 6.7 Hz), 0.98(3H, d, J 6.4 Hz), 1.20 (3H, s) and 1.26 (3H, s) both superimposed on1.07-1.74 (6H, m), 1.99-2.04 (2H, m), 2.16-2.24 (1H, m), 2.82 and 2.92(3H, s+s), 2.92 (1H, m), 3.21 and 3.23 (3H, s+s), 3.46-3.56 (1H, m),4.28 and 4.76 (ABq, J 15.2 Hz) with 4.32 and 4.76 (ABq, J 15.7 Hz)(total 2H), 5.01 (1H, d, J 17.6 Hz), 5.32 (1H, d, J 10.2 Hz), 5.72 (1H,d, J 9.9 Hz), 6.79-6.90 (1H,m), 7.22-7.31 (5H, m).

Step 2. Mutilin-14-(N,N-dimethylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N,N-dimethylcarbamate) (158 mg, 0.40 mmol) in dioxane (3 ml) wastreated with a saturated solution of zinc chloride in conc. HCl (0.5 ml)as described in Example 1 Step 2. The title compound was isolated as asolid (74 mg, 49%); ν_(max) (CH₂ Cl₂) 3564,2933, 1734, 1692, and 1454cm⁻¹ ; ¹ H NMR (CDCl₃) 0.73 (3H, d, J 6.4 Hz), 0.84 (3H, d, J 7.1 Hz),1.16 (3H, s) and 1.36 (1H, d, J 16.0 Hz) and 1.45 (3H, s) allsuperimposed on 1.08-1.80 (5H, m), 2.00-2.10 (2H, m), 2.18-2.26 (2H, m),2.37 (1H, quint., J 6.9 Hz), 2.86 (3H, s), 2.90 (3H, s), 3.34 (1H, dd, J11.3, 6.6 Hz), 5.20 (1H, dd, J 17.4, 1.7 Hz), 5.36 (1H, dd, J 11.0, 1.6Hz), 5.67 (1H, d, J 8.4 Hz), 6.65 (1H, dd, J 17.4, 11.0 Hz); MS (EI) m/z391 (M⁺); MS (NH₃ DCI) m/z 392 (MH⁺).

EXAMPLE 12 14-O-(Indolinylcarbonyl)mutilin

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-chloroformate

Method 1

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 g, 2.97 mmol)was dissolve in dry tetrahydrofuran (10 ml) under an atmosphere ofargon. The reaction was cooled to 0° C. and treated withtrichloromethylchloroformate (0.215 ml, 1.48 mmol) followed bytriethylamine (0.495 ml, 3.56 mmol). The heterogeneous mixture wasstirred at room temperature for 2 hours and then treated with furthertrichloromethylchloroformate (0.215 ml, 1.48 mmol) and triethylamine(0.495 ml, 3.56 mmol). After a further two hours moretrichloromethylchloroformate (0.108 ml, 0.74 mmol) and triethylamine(0.250 ml, 1.78 mmol) were added. The reaction was diluted withtetrahydrofuran (30 ml) and toluene (10 ml). After washing withsaturated sodium chloride the organic phase was separated and dried(MgSO₄). Removal of solvent gave a yellow oil which crystallised onstanding (1.42 g, quant). Purification of a portion of this solid (286mg) was accomplished by chromatography on silica gel, loading andeluting with 1:19 ethyl acetate-hexane. The title compound was isolateas a white crystalline solid (145 mg, 62%); ν_(max) (CH₂ Cl₂) 1765,1732, 1699, and 1458 cm⁻¹ ; ¹ H NMR (d₆ -acetone) 0.94 (3H, d, J 6.8Hz), 1.00 (3H, d, J 6.4 Hz), {1.21 (3H, s) 1.27 (3H, s), 1.78 (1H, d, J11.3 Hz), 1.91 (1H, d, 15.7 Hz)} all superimposed on 1.11-2.26 (9H, m),2.63 (1H, dd, J 15.6, 10.3 Hz), 2.82 (1H, q, obscured by HOD), 3.14 (3H,s), 3.49-3.53 (1H, m), 5.02 (1H, d, J 17.6 Hz), 5.35 (1H, d, J 10.7 Hz),5.83 (1H, d, J 10.2 Hz), 6.52 (1H, dd, J 17.6, 10.7 Hz).

Method 2

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 g, 2.97 mmol)was dissolved in toluene under an atmosphere of argon. The solution wascooled to 0° C. and treated with phosgene (2.82 ml of 12.5% w/w solutionin toluene, 3.56 mmol) followed by pyridine (0.24 ml, 2.97 mmol). Theheterogeneous reaction mixture was stirred at room temperature. After 2and 12 hour intervals the same quantities of phosgene and pyridine wereadded. The reaction mixture was then diluted with toluene (40 ml) andwashed with saturated sodium chloride solution adding just enough waterto completely dissolve all the solid in the aqueous phase. After drying(MgSO₄) the material was purified by chromatography on silica gel togive the title compound as a crystalline solid (926 mg, 78%).

Step 2.(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-14-O-(indolinylcarbonyl)-4-epi-mutilin

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-)-4-epi-mutilin 14-chloroformate(300 mg, 0.75 mmol) was dissolved in dry CH₂ Cl₂ whilst under anatmosphere of argon. The solution was treated with indoline (268 mg, 2.2mmol) and the reaction stirred at room temperature for 15 minutes. Themixture was diluted with CH₂ Cl₂ and washed sequentially with 1.0M HClfollowed by water and saturated sodium chloride solution. The organicphase was dried (MgSO₄) and the solvents removed by evaporation underreduced pressure. Purification was achieved by chromatography on silicagel loading and eluting with 1:9 ethyl acetate-hexane. The titlecompound was isolated as a foam (308 mg, 86%); ν_(max) (CH₂ Cl₂) 2930,1731, 1696, and 1602 cm⁻¹ ; ¹ H NMR (d₆ -acetone) 0.85-0.91 (3H, m),1.02 (3H, d, J 6.4 Hz), 1.11-1.79 (14H, m), 1.90-2.23 (3H, m), 2.42-2.63(1H, m), 3.01 (1H, q, J 6.4 Hz), 3.18-3.27 (1H, m), 3.50-3.59 (1H, m),4.04-4.18 (2H, m), 4.99 (1H, d, J 17.6 Hz), 5.30 (1H, d, J 10.8 Hz),5.83-5.87 (1H, m), 6.82-6.99 (m), 7.16-7,23 (m), 7.88-7.91 (m) (total4H); MS (EI) m/z 479 (M⁺), (NH₃ DCI) m/z 480 (MH⁺).

Step 3: 14-O-(Indolinylcarbonyl)mutilin

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-14-O-(indolinylcarbonyl)-4-epi-mutilin(260 mg, 0.54 mmol) in dioxane (5 ml) was treated with a saturatedsolution of zinc chloride in conc. HCl (0.5 ml) as described in Example1 Step 2. The title compound was isolated as a solid which wascrystallised from CH₂ Cl₂ --hexane (195 mg, 77%); ν_(max) (CH₂ Cl₂)3627. 3563, 2934, 1734, 1697, 1602, 1487, and 1407 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.76 (3H, m), 0.89 (3H, d, J 7.1 Hz), 1.06-1.83 (16H, m),2.14-2.29 (4H, m), 2.44 (1H, quint, J 6.9 Hz), 3.12 (2H, t, J 8.6 Hz),3.38 (1H, m), 3.94-4.04 (1H, m), 5.22 (1H, dd, J 17.5, 1.5 Hz), 5.38(1H, dd, J 11.0, 1.5 Hz), 5.72-5.86 (1H, m), 6.58-6.64 (1H, m),6.92-6.98 (m), 7.19-7.22 (m), 7.89-7.92 (m) (total 4H); MS (EI) m/z 465(M⁺). C₂₉ H₃₉ NO₄ requires 465.2879, Found: 465.2885.

EXAMPLE 13 Mutilin 14-[N-(2-Hydroxyethyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2-hydroxyethyl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(300 mg, 0.75 mmol) (prepared as described in Example 12, Step 1, Method2) was dissolved in dry dichloromethane (5 ml) and treated withethanolamine (0.137 ml, 2.25 mmol) and reacted as described in Example,Step 1. The title compound was isolated as a foam (323 mg, quant.);ν_(max) (CH₂ Cl₂) 3616, 3446, 2931, 1699, and 1513 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.85 (3H, d, J 6.9 Hz), 0.98 (3H, d, J 6.4 Hz), 1.23 (6H, s),1.61 (1H, d, exchange in D₂ O) superimposed on 0.95-1.72 (7H, m),1.93-2.04 (2H, m), 2.14-2.36 (1H, m), 2.41 (1H, dd, J 15.2, 10.1 Hz),2.93 (1H, q, J 6.4 Hz), 3.22 (3H, s), 3.37-3.48 (3H, m), 3.72 (2H, m,collapses to t in D₂ O, J 5.0 Hz), 5.00 (1H, d, J 17.6 Hz) superimposedon 5.04 (1H, broad s) 5.29 (1H, d, J 10.8 Hz), 5.69 (1H, d, J 9.9 Hz),6.73 (1H, dd, J 17.5, 10.6 Hz); MS (NH₃ DCI) m/z 422 (MH⁺), m/z 439(MNH₄ ⁺).

Step 2. Mutilin 14-[N-(2-Hydroxyethyl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2-hydroxyethyl)carbamate] (300 mg, 0.56 mmol) in dioxane (5 ml)was treated with a saturated solution of zinc chloride in conc. HCl (0.5ml) as described in Example 1 Step 2. The title compound was isolated asa solid which was crystallised from CH₂ Cl₂ /hexane(108 mg, 47%);ν_(max) (CH₂ Cl₂) 3620, 3564, 3446, 2937, 1733, 1712, 1512, and 1455cm⁻¹ ; ¹ H NMR (CDCl₃) 0.76 (3H, d, J 6.4 Hz), 0.86 (3H, d, J 7.0 Hz),1.08-1.81 (16H, m) {including 1.16 (3H, s), 1.40 (3H, s)}, 2.08 (1H,broad s) superimposed in 1.98-2.13 (1H, m), 2.18-2.24 (2H, m), 2.39 (1H,quint, J 6.9 Hz), 3.31-3.38 (3H, m), 3.68 (2H, m, collapses to t in D₂O, J 5.0 Hz), 4.98 (1H, broad t), 5.20 (1H, dd, J 17.5, 1.5 Hz), 5.35(1H, dd, J 11.3, 1.5 Hz), 5.64 (1H, d, J 8.3 Hz), 6.56 (1H, dd, J 17.4,11.0 Hz); MS (EI) m/z 484 (M⁺). C₂₃ H₃₇ NO₅ requires 407.2762, Found:407.2670.

EXAMPLE 14 Mutilin 14-(N-Methyl-N-benzylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-methyl-N-benzylcarbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-)-4-epi-mutilin 14-chloroformate(300 mg, 0.75 mmol) (prepared as described in Example 12, Step 1, Method2) was dissolved in dry dichloromethane (5 ml) and treated withN-methyl-benzylamine (0.293 ml, 2.25 mmol) and reacted as described inExample, Step 1. The title compound was isolated as a foam (323 mg,90%.); ν_(max) (CH₂ Cl₂) 2981, 2929, 1698, and 1454 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.87 (3H, d, J 6.7 Hz), 0.98 (3H, d, J 6.4 Hz), 1.20 (3H, s) and1.26 (3H, s) both superimposed on 1.07-1.74 (12H, m), 1.99-2.04 (2H, m),2.16-2.24 (1H, m), 2.82 and 2.92 (3H, s+s), 2.92 (1H, m), 3.21 and 3.23(3H, s+s), 3.46-3.56 (1H, m), 4.28 and 4.76 (ABq, J 15.2 Hz) with 4.32and 4.76 (ABq, J 15.7 Hz) (total 2H), 5.01 (1H, d, J 17.6 Hz), 5.32 (1H,d, J 10.2 Hz), 5.72 (1H, d, J 9.9 Hz), 6.79-6.90 (1H,m), 7.22-7.31 (5H,m); MS (NH₃ DCI) m/z 482 (MH⁺), m/z 499 (MNH₄ ⁺); MS (EI) m/z 481 (M⁺).C₃₀ H₄₃ NO₄ requires 481.3192, Found: 481.3199.

Step 2. Mutilin 14-(N-Methyl-N-benzylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-methyl-N-benzylcarbamate) (270 mg, 0.56 mmol) in dioxane (5 ml)was treated with a saturated solution of zinc chloride in conc. HCl (0.5ml) as described in Example 1 Step 2. The title compound was isolated asa solid (187 mg, 72%); ν_(max) (CH₂ Cl₂) 3656, 3564, 2932, 1734, 1688,and 1453 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.76 (3H, d, J 5.9 Hz), 0.86 (3H, d, J7.0 Hz), 1.41-1.81 (15H, m), 1.97-2.42 (5H, m), 2.78 and 2.89 (3H, s+s),3.32-3.38 (1H, m), 4.24 and 4.34 (1H, d+d, J 15.8 Hz), 4.61 (1H, d, J15.3 Hz), 5.32 (1H, d, J 17.5 Hz), 5.38 (1H, d, J 10.8 Hz), 5.75 (1H, d,J 8.3 Hz), 6.56-6.73 (1H, m), 7.20-7.31 (5H, m); MS (EI) m/z 467 (M⁺);MS (NH₃ DCI) m/z 468 (MH⁺).

EXAMPLE 15 14-O-(Morpholinocarbonyl)mutilin

Step 1.(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-14-O-(morpholinocarbonyl)-4-epi-mutilin

Morpholine (0.2 ml, 2.29 mmol) was added to a solution of(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(300 mg, 0.75 mmol) (Example 12, Step 1, Method 2) in dichloromethane (5ml) under an atmosphere of argon. After two days the reaction wasdiluted with dichloromethane and washed with 1M HCl. The organic phasewas dried (MgSO₄) and the solvent removed to afford the crude product.Chromatography on silica gel afforded the title compound (193 mg, 57%);ν_(max) (CH₂ Cl₂) 1691 cm⁻¹, ¹ H NMR (CDCl₃) 6.79 (1H, dd, J 17.6, 10.7Hz), 5.86 (1H, d, J 9.9 Hz), 5.31 (1H, d, J 10.7 Hz), 5.01 (1H, d, J17.6 Hz), 3.66 (4H, m), 3.49 (5H, m), 3.22 (3H, s), 2.93 (1H, q, J 6.4Hz), 2.43 (1H, dd, J 15.2, 10.0 Hz), 2.20 (1H, m ), 1.99 (2H, m), 1.72(1H, d, J 11.3 Hz), 1.63 (1H, d, J 15.2 Hz), 1.52-1.20 (5H, m), 1.23(3H,s), 1.20 (3H, s), 1.09 (1H, m), 0.98 (3H, d, J 6.4 Hz), 0.89 (3H, d,J 6.9 Hz), MS(EI), m/z 447 (M⁺) Found: 447.2990, C₂₆ H₄₁ NO₅ requires447.2985.

Step 2. 14-O-(Morpholinocarbonyl)-mutilin

The product of Step 1 (153 mg, 0.34 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (81 mg, 55%); ν_(max)(CH₂ Cl₂) 3563, 1733, and 1689 cm⁻, ¹ H NMR (CDCl₃) 6.62 (1H, dd, J17.4, 11 Hz), 5.70 (1H, d, J 8.4 Hz), 5.37 (1H, dd, J 11.0, 1.6 Hz),5.21 (1H, dd, J 17.4, 1.6 Hz), 3.62 (4H, m), 3.43 (4H, m), 3.35 (1H, d,J 11.2, 6.6 Hz), 2.36 (1H, quintet, J 7.0 Hz), 2.22 (2H, m), 2.10 (1H,br), 2.04 (1H, m), 1.81-1.57 (4H, m), 1.54-1.34 (4H, m), 1.43 (3H, s),1.19 (1H, m), 1.17 (3H, s), 0.86 (3H, d, J 7.0 Hz), 0.74 (3H, d, J 6.5Hz), MS(EI) m/z 433 (M⁺) Found: 433.2834, C₂₅ H₃₉ NO₅ requires 433.2828.

EXAMPLE 16 Mutilin 14-(N-methyl-N-phenylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-methyl-N-phenylcarbamate

N-Methylaniline (0.3 ml, 2.32 mmol) was reacted with(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(300 mg, 0.75 mmol) (Example 12, Step 1, Method 2) in dichloromethane (5ml), as for Example 12 Step 2, to afford the title compound (287 mg,81%); ν_(max) (CH₂ Cl₂) 1693 cm⁻¹ ; ¹ H NMR (CDCl₃) 7.37 (2H, m), 7.24(3H, m), 6.83 (1H, m), 5.69 (1H, m), 5.30 (1H, d, J 10.7 Hz), 5.00 (1H,d, J 17.5 Hz), 3.45 (1H, m), 3.32 (3H, s), 3.19 (3H, s), 2.92 (1H, m),2.41 (1H, m), 2.18 (1H, m), 1.99 (2H, m), 1.74-1.58 (3H, m), 1.38-1.02(11H, m), 0.97 (3H, d, J 6.4 Hz), 0.82 (3H, m); MS(EI) m/z 467 (M⁺)Found: 467.3040, C₂₉ H₄₁ NO₄ requires 467.3036.

Step 2. Mutilin 14-(N-methyl-N-phenylcarbamate)

The product of Step 1 (270 mg, 0.58 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (172 mg, 66%); ν_(max)(CH₂ Cl₂) 3562, 1734, 1691 cm⁻¹ ; ¹ H NMR (CDCl₃) 7.34 (2H, m), 7.20(3H, m), 6.64 (1H, dd, J 17.3, 11 Hz), 5.71 (1H, m), 5.38 (1H, d, J 10.7Hz), 5.23 (1H, d, J 17.6 Hz), 3.33 (1H, dd, J 11.2, 6.7 Hz), 3.28 (3H,s), 2.38-2.05 (5H, m), 1.78-1.07 (9H, m), 1.58 (3H, s), 1.18 (3H, s),0.85 (3H, d, J 7.0 Hz), 0.74 (3H, m); MS(EI) m/z 453 (M⁺) Found:453.2884, C₂₈ H₃₉ NO₄ requires 453.2879.

EXAMPLE 17 Mutilin 14-[N-(3-dimethylaminopropyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-dimethylaminopropyl)carbamate]

3-Dimethylaminopropylamine (0.07 ml, 0.56 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(170 mg, 0.43 mmol) in dichloromethane (3 ml), as for Example 12 Step 2,to afford the title compound (147 mg, 74%); ν_(max) (CH₂ Cl₂) 3447, 1698cm⁻¹, ¹ H NMR (CDCl₃) 6.78 (1H, dd, J 17.5, 10.7 Hz), 5.62 (1H, dd, J9.9 Hz), 5.52 (1H, m), 5.29 (1H, d, J 10.7 Hz), 4.99 (1H, d, J 17.5 Hz),3.48-3.15 (3H, m), 3.21 (3H, s), 2.94 (1H, q, J 6.4 Hz), 2.42 (1H, m),2.33 (2H, t, J 6.7 Hz), 2.21 (6H, s), 2.16 (1H, m), 1.98 (2H, m), 1.83(1H, br), 1.67 (5H, m), 1.47 (1H, m), 1.30-1.05 (3H, m), 1.18 (6H, s),0.97 (3H, d, J 6.4 Hz), 0.85 (3H, d, J 6.9 Hz), MS(EI) m/z 462 (M⁺)Found: 462.3457, C₂₇ H₄₆ N₂ O₄ requires 462.3458.

Step 2. Mutilin 14-[N-(3-dimethylaminopropyl)carbamate]

The product of Step 1 (141 mg, 0.3 mmol) in dioxane (3 ml) was treatedwith concentrated HCl (1 ml), and stirred at room temperature for 24 h.The reaction was carefully partitioned between ethyl acetate andsaturated sodium hydrogen carbonate and the aqueous phase reextractedwith ethyl acetate. The combined organics were dried (MgSO₄) andconcentrated to afford the title compound (123 mg, 90%); ν_(max) (CH₂Cl₂) 3447, 1733, 1708 cm⁻¹ ; ¹ H NMR (CDCl₃) 6.61 (1H, dd, J 17.4, 11.0Hz), 5.63 (1H, d, J 8.4 Hz), 5.35 (2H, includes 1H, dd, J 11.0, 1.5 Hz),5.19 (1H, dd, J 17.4, 1.6 Hz), 3.22 (3H, m), 2.35 (4H, m), 2.19 (6H, s),2.00 (2H, m), 1.68 (7H, m), 1.42 (7H, m), 1.16 (3H, s), 1.15 (1H, m),0.85 (3H, d, J 7.0 Hz), 0.76 (3H, d, J 6.0 Hz): MS(EI) m/z 448 (M⁺)Found: 448.3302, C₂₆ H₄₄ N₂ O₄ requires 448.3301.

EXAMPLE18 Mutilin 14-(N-hydroxycarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-hydroxycarbamate)

Hydroxylamine hydrochloride (50 mg, 0.72 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(150 mg, 0.38 mmol) and diisopropylethylamine (0.2 ml, 1.15 mmol) indichloromethane (3 ml), as for Example 12 Step 2, to afford the titlecompound (80 mg, 54%); ν_(max) (CH₂ Cl₂) 3534, 1720, 1698 cm⁻¹ ; ¹ H NMR(CDCl₃) 7.18 (1H, s), 6.67 (2H includes 1H, dd, J 17.5, 10.6 Hz), 5.73(1H, d, J 9.9 Hz), 5.29 (1H, d, J 10.7 Hz), 5.02 (1H, d, 17.5 Hz), 3.44(1H, ddd, J 11.2, 8.0, 5.4 Hz), 3.21 (3H, s), 2.89 (1H, q, J 6.4 Hz),2.45 (1H, dd, J 15.2, 10.1 Hz), 2.19 (1H, m), 1.99 (2H, m), 1.72 (1H, d,J 11.3 Hz), 1.62 (1H, d, J 15.2 Hz), 1.49 (2H, m), 1.35-1.03 (4H, m),1.19 (6H, s), 0.99 (3H, d, J 6.4 Hz), 0.84 (3H, d, J 6.9 Hz); MS(3 NOBAsodium) m/z 416 (MNa⁺).

Step 2. Mutilin 14-(N-hydroxycarbamate)

The product of Step 1 (72 mg, 0.18 mmol) in dioxane (3 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (47 mg, 68%); ν_(max)(KBr disc) 3418, 1728 cm⁻¹, ¹ H NMR (CDCl₃) 9.38 (1H, s), 8.59 (1H, s),6.24 (1H, dd, J 17.7, 11.1 Hz), 5.46 (1H, d, J 8.0 Hz), 5.11 (1H, dd, J17.7, 1.8 Hz), 5.04 (1H, dd, J 11.2, 1.9 Hz), 4.46 (1H, d, J 6.1 Hz),3.40 (1H, m,), 2.36 (1H,br s), 2.09 (4H, m), 1.65 (2H, m), 1.49 (2H, m),1.33 (3H, s), 1.26 (3H, m), 1.06 (4H, includes 3H, s), 0.81 (3H, d, J6.8 Hz), 0.67 (3H,br d, J 5.7 Hz); MS(CI) m/z 397 (MNH₄ ⁺).

EXAMPLE 19 Mutilin 14-(N-methoxycarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-methoxycarbamate)

Methoxylamine hydrochloride (70 mg, 0.84 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(167 mg, 0.42 mmol) and diisopropylethylamine (0.22 ml, 1.26 mmol) indichloromethane (3 ml), as for Example 12 Step 2, to afford the titlecompound (164 mg, 96%); ν_(max) (CH₂ Cl₂) 3379, 1742, 1698 cm⁻¹, ¹ H NMR(CDCl₃) 7.39 (1H, s), 6.70 (1H, dd, J 17.5, 10.7 Hz), 5.73 (1H, d, J10.0 Hz), 5.29 (1H, d, J 10.7 Hz), 5.00 (1H, d, 17.5 Hz), 3.75 (3H,s),3.46 (1H, ddd, J 11.2, 4.9, 2.9 Hz), 3.21 (3H, s), 2.90 (1H, q, J 6.4Hz), 2.46 (1H, dd, J 15.3, 10.1 Hz), 2.19 (1H, m), 2.00 (2H, m), 1.72(1H, d, J 11.3 Hz), 1.65 (1H, d, J 15.3 Hz), 1.57 (2H, m), 1.36-1.06(4H, m), 1.21 (3H, s), 1.19 (3H, s), 0.99 (3H, d, J 6.4 Hz), 0.86 (3H,d, J 6.9 Hz); MS(EI) m/z 407 (M⁺) Found: 407.2670, C₂₃ H₃₇ NO₅ requires407.2672.

Step 2. Mutilin 14-(N-methoxycarbamate)

The product of Step 1 (144 mg, 0.35 mmol) in dioxane (3 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (98 mg, 70%); ν_(max)(CH₂ Cl₂) 3379, 1735 cm⁻¹, ¹ H NMR (CDCl₃) 7.28 (1H, s), 6.54 (1H, dd, J17.4, 11.0 Hz), 5.71 (1H, d, J 8.5 Hz), 5.37 (1H, dd, J 11.0, 1.5 Hz),5.22 (1H, dd, J 17.4, 1.5 Hz), 3.71 (3H, s), 3.35 (1H, dd, J 10.8, 6.7Hz), 2.34 (1H, quintet, J 6.9 Hz), 2.23 (2H, m), 2.08 (2H, m), 1.71 (4H,m), 1.46-1.38 (4H, m), 1.42 (3H, s), 1.18 (3H, s), 1.15 (1H, m), 0.88(3H, d, J 7.1 Hz), 0.78 (3H, d, J 6.6 Hz), MS(CI) m/z 411 (MNH₄ ⁺), 394(MH⁺).

EXAMPLE 20 Mutilin 14-(N-dimethylaminocarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-dimethylaminocarbamate)

1,1-Dimethylhydrazine (0.04 ml, 0.52 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(167 mg, 0.42 mmol) and diisopropylethylamine (0.15 ml, 0.86 mmol) indichloromethane (3 ml), as for Example 12 Step 2, to afford the titlecompound (130 mg, 73%); ν_(max) (CH₂ Cl₂) 3330, 1729, 1696 cm⁻¹, ¹ H NMR(CDCl₃) 6.78 (1H, dd, J 17.5, 10.7 Hz), 5.66 (1H, d, J 9.9 Hz), 5.54(1H, br s), 5.26 (1H, d, J 10.7 Hz), 4.98 (1H, d, 17.5 Hz), 3.46 (1H,ddd, J 11.2, 4.7, 2.9 Hz), 3.21 (3H, s), 2.92 (1H, q, J 6.4 Hz), 2.58(6H,s), 2.40 (1H, dd, J 14.9, 10.2 Hz), 2.18 (1H, m), 1.98 (2H, m), 1.64(3H, m), 1.53-1.05 (5H, m), 1.18 (6H, s), 0.98 (3H, d, J 6.4 Hz), 0.84(3H, d, J 6.9 Hz); MS(EI) m/z 420 (M⁺) Found: 420.2994, C₂₄ H₄₀ N₂ O₄requires 420.2988.

Step 2. Mutilin 14-(N-dimethylaminocarbamate)

The product of Step 1 (114 mg, 0.27 mmol) in dioxane (3 ml) was treatedwith concentrated HCl (1 ml), as for Example 17 Step 2, to afford thetitle compound (98 mg, 89%); ν_(max) (CH₂ Cl₂) 3330, 1732 cm⁻¹, ¹ H NMR(CDCl₃) 6.60 (1H, dd, J 17.4, 11.0 Hz), 5.65 (1H, d, J 8.4 Hz), 5.41(1H, br s), 5.34 (1H, dd, J 11.0, 1.5 Hz), 5.19 (1H, dd, J 17.4, 1.5Hz), 3.34 (1H, dd, J 10.9, 6.6 Hz), 2.55 (6H, s), 2.36 (1H, quintet, J6.9 Hz), 2.22 (2H, m), 2.03 (2H, m), 1.81-1.59 (4H, m), 1.42 (7H, m),1.16 (3H, s), 1.12 (1H, m), 0.87 (3H, d, J 7.0 Hz), 0.76 (3H, d, J 6.2Hz); MS(EI) m/z 406 (M⁺) Found: 406.2838, C₂₃ H₃₈ N₂ O₄ requires406.2832.

EXAMPLE 21 Mutilin 14-[N-(methanesulphonylamino)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11 oxo-4-epi-mutilin14-[N-(methanesulphonylamino)carbamate]

Methanesulphonyl hydrazide (94 mg, 0.85 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(170 mg, 0.43 mmol), diisopropylethylamine (0.19 ml, 1.09 mmol) and4-dimethylaminopyridine (catalytic amount) in dichloromethane (3 ml), asfor Example 12 Step 2, to afford the title compound (179 mg, 89%);ν_(max) (CH₂ Cl₂) 3372, 1716, 1698 cm⁻¹, ¹ H NMR (CDCl₃) 6.63 (1H, dd, J17.5, 10.7 Hz), 5.85 (1H, d, J 10.1 Hz), 5.31 (1H, d, J 10.7 Hz), 5.03(1H, d, 17.5 Hz), 4.32 (2H, s), 3.47 (1H, ddd, J 11.3, 8.1, 5.3 Hz),3.33 (3H, s), 3.22 (3H, s), 2.87 (1H, q, J 6.4 Hz), 2.57 (1H, dd, J15.3, 10.1 Hz), 2.21 (1H, m), 2.00 (2H, m), 1.76 (1H, d, J 11.3 Hz),1.67 (1H, d, J 15.3 Hz), 1.54-1.05 (6H, m), 1.33 (3H, s), 1.21 (3H, s),1.00 (3H, d, J 6.4 Hz), 0.87 (3H, d, J 6.9 Hz); MS(EI) m/z 470 (M⁺).

Step 2. Mutilin 14-[N-(methanesulphonylamino)carbamate]

The product of Step 1 (124 mg, 0.26 mmol) in dioxane (3 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (102 mg, 85%); ν_(max)(CH₂ Cl₂) 3371, 1733 cm⁻¹, ¹ H NMR (CDCl₃) 6.48 (1H, dd, J 17.4, 11.0Hz), 5.81 (1H, d, J 8.6 Hz), 5.37 (1H, dd, J 11.0, 1.4 Hz), 5.23 (1H,dd, J 17.4, 1.4 Hz), 4.28 (2H, s), 3.37 (1H, dd, J 10.6, 6.7 Hz), 3.29(3H, s), 2.24 (4H, m), 2.12 (1H, br s), 1.81-1.41 (8H, m), 1.59 (3H, s),1.19 (3H, s), 1.17 (1H, m), 0.89 (3H, d, J 7.0 Hz), 0.77 (3H, d, J 6.8Hz); MS(CI) m/z 474 (MNH₄ ⁺).

EXAMPLE 22 Mutilin 14-(N-methanesulphonylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-methanesulphonylcarbamate)

Methanesulphonamide (80 mg, 0.84 mmol) in DMF (0.5 ml) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(170 mg, 0.43 mmol), diisopropylethylamine (0.19 ml, 1.09 mmol) and4-dimethylaminopyridine (catalytic amount) in dichloromethane (3 ml), asfor Example 12 Step 2, to afford the title compound (191 mg, 98%);ν_(max) (CH₂ Cl₂) 3364, 1742, 1698 cm⁻¹, ¹ H NMR (CDCl₃) 6.59 (1H, dd, J17.5, 10.7 Hz), 5.80 (1H, d, J 10.0 Hz), 5.31 (1H, d, J 10.7 Hz), 5.07(1H, d, 17.5 Hz), 3.44 (1H, ddd, J 11.2, 8.2, 5.5 Hz), 3.32 (3H, s),3.22 (3H, s), 2.86 (1H, q, J 6.4 Hz), 2.52 (1H, dd, J 15.4, 10.1 Hz),2.20 (1H, m), 1.99 (2H, m), 1.74 (1H, d, J 11.3 Hz), 1.66 (1H, d, J 15.4Hz), 1.55-1.05 (6H, m), 1.23 (3H, s), 1.21 (3H, s), 1.03 (3H, d, J 6.4Hz), 0.88 (3H, d, J 6.9 Hz); MS(EI) m/z 455 (M⁺).

Step 2. Mutilin 14-(N-methanesulphonylcarbamate)

The product of Step 1 (144 mg, 0.32 mmol) in dioxane (3 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (113 mg, 81%); ν_(max)(CH₂ Cl₂) 3366, 1737 cm⁻¹, ¹ H NMR (CDCl₃) 6.45 (1H, dd, J 17.4, 11.0Hz), 5.75 (1H, d, J 8.5 Hz), 5.37 (1H, dd, J 11.0, 1.3 Hz), 5.23 (1H,dd, J 17.4, 1.4 Hz), 3.36 (1H, dd, J 10.4, 6.7 Hz), 3.27 (3H, s), 2.24(4H, m), 2.09 (1H, br s), 1.81-1.40 (8H, m), 1.43 (3H, s), 1.20 (3H, s),1.19 (1H, m), 0.89 (3H, d, J 7.0 Hz), 0.78 (3H, d, J 6.8 Hz); MS(CI) m/z459 (MNH₄ ⁺).

EXAMPLE 23 Mutilin 14-(N-benzoylaminocarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-benzoylaminocarbamate)

Benzoic hydrazide(90 mg, 0.66 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(130 mg, 0.33 mmol), diisopropylethylamine (0.17 ml, 0.98 mmol) indichloromethane (3 ml), as for Example ? Step 1, to afford the titlecompound (163 mg, 100%); ν_(max) (CH₂ Cl₂) 3403, 1729, 1696 cm⁻¹, ¹ HNMR (CDCl₃) 8.12 (1H, br), 7.82 (2H, d, J 7.3 Hz), 7.56 (1H, t, J 7.3Hz), 7.45 (2H, t, J 7.4 Hz), 6.84 (1H, br), 6.68 (1H, dd, J 17.5, 10.7Hz), 5.73 (1H, d, J 9.9 Hz), 5.26 (1H, d, J 10.7 Hz), 5.00 (1H, d, 17.5Hz), 3.44 (1H, m), 3.22 (3H, s), 2.89 (1H, q, J 6.4 Hz), 2.47 (1H, dd, J15.2, 10.0Hz), 2.19 (1H, m), 2.01 (2H, m), 1.75-1.20 (13H, m), 1.12 (1H,m), 0.98 (3H, d, J 6.4 Hz), 0.94 (3H, br d, J 6.5 Hz); MS(EI) m/z 496(M⁺).

Step 2. Mutilin 14-(N-benzoylaminocarbamate)

The product of Step 1 (153 mg, 0.31 mmol) in dioxane (3 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (110 mg, 67%); ν_(max)(CH₂ Cl₂) 3405, 1734, 1691 cm⁻¹, ¹ H NMR (CDCl₃) 8.14 (1H, br), 7.79(2H, d, J 7.2 Hz), 7.54 (1H, t, J 7.3 Hz), 7.43 (2H, t, J 7.4 Hz), 6.80(1H, br), 6.52 (1H, dd, J 17.4, 11.1 Hz), 5.69 (1H, d, J 8.5 Hz), 5.34(1H, dd, J 11.3 Hz), 5.23 (1H, dd, J 17.4 Hz), 3.36 (1H, dd, J 10.7, 6.5Hz), 2.27 (3H, m), 2.07 (2H, m), 1.80-1.43 (8H, m), 1.61 (3H, s), 1.19(3H, s), 1.18 (1H, m), 0.87 (6H, d, J 6.9 Hz); MS(EI) m/z 482 (M⁺).

EXAMPLE 24 Mutilin 14-(N-benzoylcarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-benzoylcarbamate)

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)was reacted with benzoyl isocyanate (0.25 ml, 2.0 mmol) indichloromethane (5 ml), as for Example 1 Step 1, to afford the titlecompound (478 mg, 99%); ν_(max) (CH₂ Cl₂) 3423, 1777, 1714 1698 cm⁻¹, ¹H NMR (CDCl₃) 7.99 (1H, br s), 7.83 (2H, d, J 7.0 Hz), 7.61 (1H, t, J7.3 Hz), 7.50 (2H, m), 6.73 (1H, dd, J 17.4, 10.6 Hz), 5.85 (1H, d, J9.9 Hz), 5.30 (1H, d, J 10.7 Hz), 5.02 (1H, d, 17.5 Hz), 3.47 (1H, ddd,J 11.2, 8.3, 5.3 Hz), 3.23 (3H, s), 2.91 (1H, q, J 6.4 Hz), 2.54 (1H,dd, J 15.3, 10.1Hz), 2.21 (1H, m), 2.01 (2H, m), 1.75 (1H, d, J 11.2Hz), 1.73 (1H, d, J 15.3 Hz), 1.62-1.08 (6H, m), 1.32 (3H, s), 1.21 (3H,s), 1.01 (3H, d, J 6.4 Hz), 0.91 (3H, d, J 6.9 Hz); MS(EI) m/z 481 (M⁺)Found: 481.2823, C₂₉ H₃₉ NO₅ requires 481.2828.

Step 2. Mutilin 14-(N-benzoylcarbamate)

The product of Step 1 (370 mg, 0.77 mmol) in dioxane (3 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (208 mg, 58%); ν_(max)(CH₂ Cl₂) 3429, 1779, 1733 cm⁻¹, ¹ H NMR (CDCl₃) 7.96 (1H, s), 7.80 (2H,d, J 7.1 Hz), 7.59 (1H, t, J 7.3 Hz), 7.48 (2H, t, J 7.4 Hz), 6.56 (1H,dd, J 17.4, 11.0 Hz), 5.84 (1H, d, J 8.5 Hz), 5.38 (1H, dd, J 11.0, 1.5Hz), 5.24 (1H, dd, J 17.4, 1.5 Hz), 3.77 (1H, dd, J 10.9, 6.6 Hz), 2.35(1H, quintet, J 7.0 Hz), 2.19 (4H, m), 1.82-1.30 (8H, m), 1.52 (3H, s),1.20 (3H, s), 1.13 (1H, m), 0.89 (3H, d, J 7.0 Hz), 0.81 (3H, d, J=6.6Hz); MS(CI) m/z 485 (MNH₄ ⁺).

EXAMPLE 25 Antibacterial Activity

The following Table illustrates the antibacterial activities ofrepresentative 14-carbamate derivatives, in comparison with tiamulin.Activities are given as minimum inhibitory concentrations (10⁻⁶ g/ml),and were determined using a standard broth dilution method inmicrotitre.

    ______________________________________                                        Or-          mutilin 14-                                                                             mutilin 14-(N-                                                                           mutilin 14-(N-                                gan-  carbamate hydroxy)carbamate benzoyl)carbamate                           ism tiamulin (Example 7) (Example 18) (Example 24)                          ______________________________________                                        B.f. 1       0.25      1          <0.06                                         E.c. 16 2 0.5 0.5                                                             H.i. 2 2 1 2                                                                  M.c. <0.06 <0.06 <0.06 <0.06                                                  E.f. >64 4 >64 >64                                                            S.a. 0.25 0.5 0.5 0.125                                                       S.e. 0.125 0.125 0.5 <0.06                                                    S. ag. <0.06 0.5 0.25 <0.06                                                   S. pn. <0.06 0.5 1 <0.06                                                      S.p. <0.06 0.25 1 <0.06                                                     ______________________________________                                         B.f. = Bacteroides fragilis B70;                                              E.c. = Escherichia coli DC2;                                                  H.i. = Haemophilus influenzae Q1;                                             M.c. = Moraxella catarrhalis 1502;                                            E.f. = Enterococcus faecalis I;                                               S.a. = Staphylococcus aureus Oxford;                                          S.e. = Staphylococcus epidermidis PHLN 20;                                    S. ag. = Streptococcus agalactiae Hester;                                     S. pn. = Streptococcus pneumoniae 1761;                                       S.p. = Streptococcus pyogenes CN 10.                                     

EXAMPLE 26 Mutilin 14-[N-(2-phenylethyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2-phenylethyl)carbamate]

Phenethylamine (0.16 ml, 1.29 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(170 mg, 0.43 mmol) in dichloromethane (5 ml), as described in Example12, Step 2, to afford the title compound (200 mg, 97%); ν_(max) (CH₂Cl₂) 2902, 2254, 1794, 1703, 1644, and 1465 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.84(3H, d, J 6.9 Hz), 0.97 (3H, d, J 6.4 Hz), 1.05-2.27 (12H, m) including1.14 (3H, s) and 1.18 (3H, s), 2.38 (1H, dd, J 15.3, 10.0 Hz), 2.82 (1H,dd, J 13.2, 6.9 Hz), 2.94 (1H, q, J 6.4 Hz), 3.21 (3H, s), 3.37-3.61(3H, m), 4.65 (1H, broad t), 5.00 (1H, d, J 17.5 Hz), 5.31 (1H, d, J10.6 Hz), 5.64 (1H, d, J 9.8 Hz), 6.75 (1H, dd, J 17.8, 10.7 Hz),7.18-7.34 (5H, m); MS (NH₃ DCI) m/z 482 (MH⁺).

Step 2. Mutilin 14-[N-(2-phenylethyl)carbamate]

The product of Step 1 (200 mg, 0.42 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (0.5 ml), as forExample 1, Step 2, to afford the title compound (75 mg, 39%); ν_(max)(CH₂ Cl₂) 3445, 1733, 1712, and 1635 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.75 (3H,broad s), 0.86 (3H, d, J 7.0 Hz), 1.06-2.23 (18H, m) including 1.16 (3H,s) and 1.35 (3H, s), 2.37 (1H, quint., J 6.6 Hz), 2.77 (1H, q, J 6.5Hz), 3.30-3.51 (3H, m), 4.11 (2H, q, J 7.2 Hz), 4.66 (1H, broad s), 5.21(1H, dd, J 17.3, 1.2 Hz), 5.35 (1H, d, J 10.8 Hz), 5.64 (1H, d, J 8.3Hz), 6.58 (1H, dd, J 17.4, 10.9 Hz), 7.14-7.31 (5H, m); MS(EI) m/z 467(M⁺), MS (NH₃ DCI) m/z 468 (MH⁺).

EXAMPLE 27 Mutilin 14-[N-(1 (R)-phenyl-2-hydroxy)ethylcarbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-(R)-phenyl-2-hydroxy)ethylcarbamate]

(R)-2-Phenylglycinol (177 mg, 1.29 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(170 mg, 0.43 mmol) in dichloromethane (5 ml), as described in Example12, Step 2, to afford the title compound (220 mg, quant.); ν_(max) (CH₂Cl₂) 3600, 3433, 2931, 1698, and 1503 cm⁻¹, ¹ H NMR (CDCl₃) 0.82 (3H, d,J 6.6 Hz), 0.95 (3H, d, J 6.4 Hz), 0.98-2.22 (18H, m), 2.43 (1H, dd, J15.3, 10.0 Hz), 2.87 (1H, q, J 6.5 Hz), 3.23 (3H, s), 3.46 (1H, s), 3.89(2H, m), 4.13 (2H, dd, J 14.3, 7.1 Hz), 4.87 (1H, broad s), 4.99 (1H, d,J 17.5 Hz), 5.27 (1H, d, J 7.3 Hz), 5.64 (1H, d, J 9.9 Hz), 6.66 (1H,dd, J 17.4, 10.6 Hz), 7.27-7.37 (5H, m).

Step 2. Mutilin 14-[N-(1-(R)-phenyl-2-hydroxy)ethylcarbamate]

The product of Step 1 (212 mg, 0.42 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (0.5 ml), as forExample 1 Step 2, to afford the title compound (81 mg, 39%); ν_(max)(CH₂ Cl₂) 3565, 3433, 2961, 1732, 1713, and 1503 cm⁻¹ ; ¹ H NMR (CDCl₃)0.73 (3H, broad d), 0.84 (3H, d, J 7.0 Hz), 0.97-1.76 (18H, m),1.93-2.30 (3H, m), 2.32 (1H, quint., J 6.6 Hz), 3.25-3.40 (1H, m),3.70-3.95 (2H, m), 4.75-4.87 (1H, broad s), 5.15-5.35 (3H, m), 5.62 (1H,d, J 8.3 Hz), 7.27-7.37 (5H,m); MS(EI) m/z 483 (M⁺), (NH₃ DCI) m/z 484(MH⁺).

EXAMPLE 28 Mutilin 14-[N-2-(methoxycarbonyl)ethylcarbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-2-(methoxycarbonyl)ethylcarbamate]

β-Alanine methyl ester hydrochloride (120 mg, 0.86 mmol) was reactedwith (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-chloroformate (170 mg, 0.43 mmol) and N,N-diisopropylethylamine(0.150 ml, 0.86 mmol) in dichloromethane (5 ml), as described in Example12, Step 2, to afford the title compound (185 mg, 93%); ν_(max) (CH₂Cl₂) 3446, 2930, 1733, 1709, 1509, and 1456 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.81(3H, d, J 6.9 Hz), 0.97 (3H, d, J 6.4 Hz), 1.04-1.71 (14H, m), 1.92-2.04(2H, m), 2.13-2.22 (1H, m), 2.39 (1H, dd, J 15.2, 10.0 Hz), 2.55 (2H, t,J 5.7 Hz), 2.92 (1H, q, J 6.4 Hz), 3.21 (3H, s), 3.41-3.54 (3H, m), 3.69(3H, s), 4.99 (1H, d, J 17.6 Hz), 5.13 (1H, t, J 6.0 Hz), 5.28 (1H, d, J10.7 Hz), 5.63 (1H, d, J 9.9 Hz), 6.74 (1H, dd, J 17.5, 10.7 Hz); MS(NH₃ DCI) m/z 464 (MH⁺), m/z 481 (MNH₄ ⁺)

Step 2. Mutilin 14-[N-2-(methoxycarbonyl)ethylcarbamate]

The product of Step 1 (200 mg, 0.42 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (0.5 ml) and thereaction stirred at room temperature overnight. The solution was pouredinto ethyl acetate and saturated sodium chloride solution. The aqueousphase was reextracted with ethyl acetate and the combined organic phaseswere washed with saturated sodium hydrogen carbonate solution (twice).The organic phase was finally washed with saturated sodium chloridesolution and dried (MgSO₄). Purification was accomplished bychromatography on silica gel, loading in dichloromethane and elutingwith mixtures of ethyl acetate in hexane. The title compound wasisolated as a foam (21 mg, 12%); ν_(max) (CH₂ Cl₂) 3564, 3446, 1734,1713, and 1509 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.71 (3H, broad d, J 6.0 Hz), 0.85(3H, d, J 7.0 Hz), 1.07-1.79 (15H, m) including 1.13 (3H, s) and 1.37(3H, s), 1.96-2.23 (4H, m), 2.35 (1H, quint., J 6.9 Hz), 2.52 (2H, t, J5.9 Hz), 3.30-3.50 (3H, m), 3.67 (3H, s), 5.06 (1H, broad t), 5.26 (1H,dd, J 17.5, 1.5 Hz), 5.34 (1H, dd, J 11.0, 1.5 Hz), 5.62 (1H, d, J 8.4Hz), 6.56 (1H, dd, J 17.4, 11.0 Hz); MS(EI) m/z 449 (M⁺), (NH₃ DCI) m/z450 (MH⁺).

EXAMPLE 29 Mutilin 14-[N-2-carboxyethylcarbamate]

Step 1. Mutilin 14-[N-2-carboxyethylcarbamate]

The sodium hydrogen carbonate solutions from Example 28, Step 2, wereacidified with hydrchloric acid (5M) and the resulting solutionextracted with ethyl acetate (twice). After washing the organic phasewith saturated sodium chloride solution it was dried (MgSO₄) and thesolvent removed by evaporation in vacuo to give the title compound as awhite solid (43 mg, 24%); ν_(max) (CH₂ Cl₂) 3446, 2961, 1730, 1714, and1509 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.72 (3H, broad d, J 5.7 Hz), 0.86 (3H, d, J7.0 Hz), 0.97-1.79 (15H, m), 1.96-2.23 (5H, m 2.55-2.60 (2H, m),3.34-3.46 (3H, m), 5.07-5.38 (3H, m), 5.61-5.68 (1H, m), 6.50-6.52 (1H,m); MS(EI) m/z 435 (M⁺); MS (NH₃ DCI) m/z 436 (MH⁺), m/z 453 (MNH₄ ⁺).

EXAMPLE 30 Mutilin 14-[N-(hydroxyiminobenzyl)carbamate]

Step 1. (3R)-3-Deoxo-11 deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(hydroxyiminobenzyl)carbamate]

Benzamidoxime (129 mg, 0.94 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(170 mg, 0.43 mmol) in dichloromethane (3 ml), as described in Example12, Step 2, to afford the title compound (180 mg, 84%); ν_(max) (CH₂Cl₂) 3519, 3414, 2930, 1759, 1697, 1640, 1586, and 1457 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.93 (3H, d. J 6.9 Hz), 1.00 (3H, d, J 6.4 Hz), 1.07-1.60 (13H,m) including 1.20 (3H, s) and 1.30 (3H, s), 1.74 (1H, d, J 11.2 Hz),1.77 (1H, d, J 15.3 Hz), 1.94-2.04 (2H, m), 2.15-2.24 (1H, m), 2.52 (1H,dd, J 15.2, 10.2 Hz), 2.88 (1H, q, J 6.4 Hz), 3.23 (3H, s), 3.43-3.54(1H, m), 4.99 (1H, d, J 17.4 Hz), 5.09 (1H, broad s), 5.27 (1H, d, J10.8 Hz), 5.70 (1H, d, J 10.0 Hz), 6.75 (1H, dd, J 17.5, 10.7 Hz),7.38-7.52 (3H, m), 7.69-7.73 (2H, m); MS (NH₃ DCI) m/z 497 (MH⁺).

Step 2. Mutilin 14-[N-(hydroxyiminobenzyl)carbamate]

The product of Step 1 (160 mg, 0.33 mmol) in dioxane (4 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (0.8 ml), as forExample 1, Step 2, to afford the title compound (114 mg, 72%); ν_(max)(CH₂ Cl₂) 3520, 3414, 2932, 1761, 1733, 1710, 1640, and 1587 cm⁻¹ ; ¹ HNMR (CDCl₃) 0.84 (3H, d, J 6.7 Hz), 0.88 (3H, d, J 7.1 Hz), 0.99-1.82(16H, m) including 1.19 (3H, s) and 1.50 (3H, s), 2.08-2.34 (4H, m)including 2.32 (1H, quint., J 6.8 Hz), 3.36 (1H, dd, J 10.5, 6.6 Hz),5.06 (2H, broad s), 5.23 (1H, dd, J 17.3, 1.5 Hz), 5.37 (1H, dd, J 11.2,1.4 Hz), 5.69 (1H, d, J 8.6 Hz), 6.57 (1H, dd, J 17.3, 11.0 Hz),7.26-7.51 (3H, m), 7.67-7.71 (2H, m); MS (NH₃ DCI) m/z 483 (MH⁺).

EXAMPLE 31 Mutilin 14-[N-(4-methoxybenzoyl)carbamate]

Step 1. 4-Methoxybenzoylisocyanate

Silver cyanate (689 mg, 4.6 mmol) was suspended in dry dichloromethane(5 ml) under an atmosphere of argon. A solution of4-methoxybenzoylchloride (682 mg, 4.0 mmol) in dichloromethane (5 ml)was added and the heterogeneous mixture stirred at reflux under subduedlight according to the method of Arcus et. al. (J. Chem. Soc. 1954,4018). After one hour the reaction was allowed to cool and filteredthrough Kieselguhr. The solution was used immediately in the nextreaction. ν_(max) (CH₂ Cl₂) 2246 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-methoxybenzoyl)carbamate]

The solution from step 1 was cooled to 0° C. and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 1 hour. The mixture was diluted withdichloromethane and washed with 1.0M hydrochloric acid followed by waterand saturated sodium chloride solution. After drying (MgSO₄) the crudematerial was purified by chromatography on silica gel, loading indichloromethane and eluting with 20% ethyl acetate in hexane.Evaporation of solvents in vacuo gave the title compound (488 mg, 95%);m.p. (CH₂ Cl₂ /hexane) 168° C.; ν_(max) (CH₂ Cl₂) 3427, 3300, 2931,1774, 1697, 1605, and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90 (3H, d, J 6.9Hz), 1.00 (3H, d, J 6.4 Hz), 1.07-1.56 (12H, m) including 1.20 (3H, s)and 1.32 (3H, s), 1.72 (1H, d, J 15.3 Hz), 1.74 (1H, d, J 11.2 Hz),1.94-2.04 (2H, m), 2.16-2.24 (1H, m), 2.53 (1H, dd, J 15.2, 10.1 Hz),2.91 (1H, q, J 6.2 Hz), 3.23 (3H, s), 3.42-3.50 (1H, m), 3.87 (3H, s),5.00 (1H, d, J 17.5 Hz), 5.29 (1H, d, J 10.7 Hz), 5.84 (1H, d, J 9.9Hz), 6.73 (1H, dd, J 17.4, 10.6 Hz), 6.97 (2H, d, J 8.9 Hz), 7.81 (2H,d, J 8.9 Hz); MS (EI) m/z 511 (MH⁺); (NH₃ DCI) m/z 512 (MH⁺); (Found: C,70.38; H, 8.21; N, 2.91. C₃₀ H₄₁ NO₆ requires C, 70.42; H, 8.08; N,2.74)

Step 3. Mutilin 14-[N-(4-methoxybenzoyl)carbamate]

The product of Step 2 (440 mg, 0.85 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (140 mg, 33%); m.p. (CH₂Cl₂ /hexane) 108° C. (dec.); ν_(max) (CH₂ Cl₂) 3564, 3429, 2961, 1776,1733, 1710, 1607, and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.81 (3H, d, J 6.6Hz), 0.88 (3H, d, J 7.0 Hz), 1.10-1.81 (15H, m) including 1.15 (3H, s)and 1.51 (3H, s), 2.12 (1H, bs) superimposed on 2.09-2.26 (2H, m), 2.35(1H, quint., J 6.9 Hz), 3.36 (1H, dd, J 11.0, 6.6 Hz), 3.86 (3H, s),5.22 (1H, dd, J 17.3, 1.5 Hz), 5.37 (1H, dd, J 11.0, 1.4 Hz), 5.83 (1H,d, J 8.5 Hz), 6.56 (1H, dd, J 17.3, 11.0 Hz), 6.95 (2H, d, J 8.8 Hz),7.77 (2H, d, J 8.8 Hz), 7.88 (1H, bs); MS (NH₃ DCI) m/z 498 (MH⁺);(Found: C, 69.88; H, 7.67; N, 2.93. C₂₉ H₃₉ NO₆ requires C, 70.00; H,7.90; N, 2.81).

EXAMPLE 32 Mutilin 14-[N-(4-nitrobenzoyl)carbamate]

Step 1. 4-Nitrobenzoylisocyanate

Silver cyanate (689 mg, 4.6 mmol) was suspended in dry dichloromethane(5 ml) under an atmosphere of argon. A solution of4-nitrobenzoylchloride (682 mg, 4.0 mmol) in dichloromethane (5 ml) wasadded and the reaction treated as described in Example 31, Step 1. Thesolution was used immediately in the next reaction.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-nitrobenzoyl)carbamate]

The solution from Step 1 was cooled to 0° C. and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 1 hour. The title compound was isolated bythe same procedure as described in Example 31, Step 2 (480 mg, 91%);ν_(max) (CH₂ Cl₂) 3406, 2959, 1780, 1733, 1698, 1607, and 1531 cm⁻¹ ; ¹H NMR (CDCl₃) 0.90 (3H, d, J 6.8 Hz), 1.03 (3H, d, J 6.4 Hz), 1.08-1.59(12H, m) including 1.20 (3H, s) and 1.31 (3H, s), 1.69 (1H, d, J 15.5Hz), 1.75 (1H, d, J 11.6 Hz), 1.93-2.05 (2H, m), 2.15-2.25 (1H, m), 2.54(1H, dd, J 15.2, 10.1 Hz), 2.89 (1H, q, J 6.4 Hz), 3.22 (3H, s),3.41-3.50 (1H, m), 5.01 (1H, d, J 17.5 Hz), 5.28 (1H, d, J 10.7 Hz),5.84 (1H, d, J 9.9 Hz), 6.64 (1H, dd, J 17.4, 10.7 Hz), 8.00 (2H, d, J8.7 Hz), 8.22 (1H, bs), 8.35 (2H, d, J 8.9 Hz); MS (NH₃ DCI) m/z 544(MNH₄ ⁺).

Step 3. Mutilin 14-[N-(4-nitrobenzoyl)carbamate]

The product of Step 2 (440 mg, 0.83 mmol) in dioxane (10 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (282 mg, 66%); ν_(max)(CH₂ Cl₂) 3551, 3412, 2959, 1786, 1734, 1699, 1607, and 1531 cm⁻¹ ; ¹ HNMR (CDCl₃) 0.80 (3H, d, J 6.8 Hz), 0.88 (3H, d, J 7.0 Hz), 1.10-1.23(4H, m), 1.41-1.82 (12H, m) including 1.50 (3H, s), 2.11 (1H, bs),2.14-2.34 (3H, m), 3.37 (1H, dd, J 10.7, 6.6 Hz), 5.24 (1H, dd, J 17.3,1.4 Hz), 5.36 (1H, dd, J 10.9, 1.3 Hz), 5.81 (1H, d, J 8.5 Hz), 6.49(1H, dd, J 17.3, 11.0 Hz), 7.94 (2H, d, J 8.8 Hz), 8.04 (1H, bs), 8.33(2H, d, J 8.8 Hz).

EXAMPLE 33 Mutilin 14-[N-(3-nitrobenzoyl)carbamate]

Step 1. 3-Nitrobenzoylisocyanate

Silver cyanate (689 mg, 4.6 mmol) was suspended in dry dichloroethane (5ml) under an atmosphere of argon. A solution of 3-nitrobenzoylchloride(682 mg, 4.0 mmol) in dichloroethane (5 ml) was added and the reactionstirred at reflux for 4 hours before treating as described in Example31, Step 1. The solution was used immediately in the next reaction.ν_(max) (CH₂ Cl₂) 2247 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-nitrobenzoyl)carbamate]

The solution from Step 1 was cooled to 0° C. and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 1 hour. The title compound was isolated bythe same procedure as described in Example 31, Step 2 (523 mg, quant.);ν_(max) (CH₂ Cl₂) 3406, 2930, 1781, 1720, 1698, 1618, and 1537 cm⁻¹ ; ¹H NMR (CDCl₃) 0.91 (3H, d, J 6.8 Hz), 1.00 (3H, d, J 6.4 Hz), 1.08-1.60(12H, m) including 1.20 (3H, s) and 1.30 (3H, s), 1.67-1.77 (2H, m),2.00-2.05 (2H, m), 2.15-2.25 (1H, m), 2.55 (1H, dd, J 15.3, 10.1 Hz),2.89 (1H, q, J 6.3 Hz), 3.22 (3H, s), 3.41-3.50 (1H, m), 5.01 (1H, d, J17.5 Hz), 5.24 (1H, d, J 10.7 Hz), 5.86 (1H, d, J 10.0 Hz), 6.62 (1H,dd, J 17.4, 10.6 Hz), 7.73 (1H, t, J 8.0 Hz), 8.20 (1H, d, J 7.9 Hz),8.23 (1H, s), 8.46 (1H, dd, J 7.8, 1.0 Hz), 8.67 (1H, m); MS (NH₃ DCI)m/z 544 (MNH₄ ⁺).

Step 3. Mutilin 14-[N-(3-nitrobenzoyl)carbamate]

The product of Step 2 (483 mg, 0.92 mmol) in dioxane (10 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (280 mg, 66%); m.p. (CH₂Cl₂ /hexane) 121° C.; ν_(max) (CH₂ Cl₂) 3564, 3418, 2940, 1782, 1733,1617, and 1537 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80 (3H, d, J 6.7 Hz), 0.88 (3H,d, J 6.9 Hz), 1.09-1.23 (4H, m), 1.40-1.81 (12H, m), 2.11 (1H, bs),2.14-2.33 (3H, m), 3.36 (1H, dd, J 10.7, 6.7 Hz), 5.23 (1H, dd, J 17.4,1.4 Hz), 5.31 (1H, dd,.J 10.9, 1.2 Hz), 5.81 (1H, d, J 8.0 Hz), 6.49(1H, dd, J 17.3, 11.0 Hz), 7.71 (1H, t, J 8.0 Hz), 8.17 (1H, dt, J 7.9,1.3 Hz), 8.29 (1H, bs), 8.43 (1H, dt, J 8.0, 1.1 Hz), 8.64 (1H, t, J 1.9Hz); MS (NH₃ DCI) m/z 530 (MNH₄ ⁺); (Found: C, 65.95; H, 7.23; N, 5.35.C₂₈ H₃₆ N₂ O₇ requires C, 65.61; H, 7.08; N, 5.46).

EXAMPLE 34 Mutilin 14-[N-(4-aminobenzoyl)carbamate]

Mutilin 14-[N-(4-nitrobenzoyl)carbamate] (79 mg, 0.15 mmol) wassuspended in ethanol (10 ml). Addition of ethyl acetate (2 ml) broughtabout complete dissolution. Tin (II) chloride (146 mg, 0.75 mmol) wasadded and the reaction warmed to reflux whilst under an atmosphere ofargon. After an hour the reaction was allowed to cool and poured intoethyl acetate/water before neutralising with sodium hydrogen carbonate.The organic phase was dried (MgSO₄) and purified by chromatography onsilica gel eluting with 50% ethyl acetate in hexane. The title compoundwas isolated as a coloured foam (44 mg, 61%); ν_(max) (CH₂ Cl₂) 3684,3405, 2933, 1782, 1773, 1733, 1605, and 1473 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80(3H, d, J 6.5 Hz), 0.88 (3H, d, J 7.0 Hz), 1.09-1.26 (4H, m), 1.40-1.81(12H, m), 2.04-2.37 (4H, m), 3.36 (1H, dd, J 10.6, 6.6 Hz), 4.13 (2H,bs), 5.22 (1H, dd, J 17.4, 1.5 Hz), 5.36 (1H, dd, J 11.0, 1.3 Hz), 5.78(1H, d, J 8.4 Hz), 6.56 (1H, dd, J 17.4, 1.0 Hz), 6.65 (2H, d, J 8.7Hz), 7.64 (2H, d, J 8.7 Hz), 7.83 (1H, bs); MS (NH₃ DCI) m/z 483 (MH⁺).

EXAMPLE 35 Mutilin 14-[N-(3-aminobenzoyl)carbamate]

Mutilin 14-[N-(3-nitrobenzoyl)carbamate] (100 mg, 0.19 mmol) wassuspended in ethanol (10 ml). Addition of ethyl acetate (2 ml) broughtabout complete dissolution. Tin (II) chloride (185 mg, 1.0 mmol) wasadded and the reaction treated as described in Example 34. The titlecompound was isolated as a coloured foam (55 mg, 60%); ν_(max) (CH₂ Cl₂)3395, 2932, 1778, 1733, 1716, 1624, and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80(3H, d, J 6.6 Hz), 0.88 (3H, d, J 7.0 Hz), 1.10-1.82 (16H, m, including1.19 (3H, s) and 1.51 (3H, s)), 2.09-2.37 (4H, m), 3.37 (1H, dd, J 10.8,6.6 Hz), 3.86 (2H, bs), 5.23 (1H, dd, J 17.4, 1.5 Hz), 5.39 (1H, dd, J11.0, 1.4 Hz), 5.82 (1H, d, J 8.5 Hz), 6.58 (1H, dd, J 17.3, 11.0 Hz),6.86 (1H, dd, J 7.8, 2.4 Hz), 7.06 (1H, d, J 7.8 Hz), 7.13 (1H, t, J 2.0Hz), 7.23 (1H, t, J 7.8 Hz), 7.88 (1H, bs); MS (ESI, -ve ion) m/z 481(M-H⁻).

EXAMPLE 36 Mutilin 14-[N-(2-hydroxybenzoyl)carbamate]

Step 1. 2-Acetoxybenzoylisocyanate

Silver cyanate (689 mg, 4.6 mmol) and O-acetylsalicoyl chloride (794 mg,4.0 mmol) in dichloroethane (10 ml) were reacted in the manner describedin Example 33, Step 1. The title compound was immediately used in thenext reaction.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2-acetoxybenzoyl)carbamate]

The solution from Step 1 was cooled to 0° C. and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-1-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 1 hour. The title compound (80% pure) wasisolated by the same procedure as described in Example 31, Step 2 (385mg, 70%); ν_(max) (CH₂ Cl₂) 3411, 2981, 2931, 1778, 1732, 1698, 1606,and 1480 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.89 (3H, d, J 6.8 Hz), 1.00 (3H, d, J6.4 Hz), 1.08-1.60 (12H, m) including 1.20 (3H, s) and 1.26 (3H, s),1.67-1.76 (2H, m), 1.95-2.05 (2H, m), 2.15-2.25 (1H, m), 2.38 (3H, s),2.50 (1H, dd, J 15.3, 10.1 Hz), 2.88 (1H, q, J 6.3 Hz), 3.22 (3H, s),3.42-3.48 (1H, m), 5.00 (1H, d, J 17.5 Hz), 5.30 (1H, d, J 10.7 Hz),5.81 (1H, d, J 10.0 Hz 6.72 (1H, dd, J 17.4, 10.6 Hz), 7.21-7.42 (2H,m), 7.68 (1H, dt, J 7.8, 1.4 Hz), 8.09 (1H, dd, J 7.9, 1.6 Hz), 8.36(1H, bs), 8.46 (1H, dd, J 7.8, 1.0 Hz), 8.67 (1H, m); MS (EI) m/z 539(MH⁺); (NH₃ DCI) m/z 540 (MH⁺).

Step 3. Mutilin 14-[N-(3-hydroxybenzoyl)carbamate]

The product of Step 2 (385 mg, 0.50 mmol of 80% pure material) indioxane (10 ml) was treated with a saturated solution of zinc chloridein conc. HCl (1 ml), as for Example 1 Step 2. The crude material wasdissolved in ethanol (2 ml) and treated with 1.0M sodium hydroxide for 1hour at room temperature. The solution was poured into ethyl acetate inhexane and water. The organic phase was washed with saturated sodiumchloride and dried (MgSO₄). Purification was accomplished bychromatography on silica gel eluting with 10% acetone in toluene. Thetitle compound was isolated as a white solid (115 mg, 47%); m.p. (CH₂Cl₂ /hexane) 170° C.; ν_(max) (CH₂ Cl₂) 3566, 3434, 2960, 1775, 1733,1673, and 1493 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.79 (3H, d, J 6.7 Hz), 0.89 (3H,d, J 6.9 Hz 1.09-1.25 (4H, m), 1.37-1.81 (12H, m), 2.11-2.33 (4H, m),3.37 (1H, dd, J 10.2, 6.6 Hz), 5.22 (1H, dd, J 17.4, 1.3 Hz), 5.35 (1H,dd, J 10.9, 1.1 Hz), 5.81 (1H, d, J 8.5 Hz), 6.52 (1H, dd, J 17.3, 11Hz), 6.90 (1H, td, J 7.5, 0.8 Hz), 7.02 (1H, dd, J 8.3, 0.9 Hz),7.18-7.28 (1H, m), 7.95 (1H, d, J 7.6 Hz), 8.45 (1H, bs), 11.31 (1H,bs); MS (ESI -ve ion) m/z 482 (M-H⁻).

EXAMPLE 37 Mutilin 14-[N-(4-Acetoxybenzoyl)carbamate]

Step 1. 4-Acetoxybenzoylisocyanate

Silver cyanate (950 mg, 6.3 mmol) and 4-acetoxybenzoyl chloride (1.09 g,5.5 mmol) in dichloroethane (10 ml) were reacted in the manner describedin Example 34, Step 1. The title compound was immediately used in thenext reaction; ν_(max) (CH₂ Cl₂) 2240 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-acetoxybenzoyl)carbamate]

The solution from Step 1 was cooled to 0° C. and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (446 mg, 1.27 mmol)and the reaction stirred for 1 hour. The title compound was isolated bythe same procedure as described in Example 31, Step 2 (620 mg, 91%);ν_(max) (CH₂ Cl₂) 3420, 2930, 1777, 1762, 1731, 1714, 1698, 1604, and1478 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.89 (3H, d, J 6.8 Hz), 1.00 (3H, d, J 6.4Hz), 1.07-1.56 (12H, m), 1.72 (1H, d, J 15.4 Hz), 1.74 (1H, d, J 11.2Hz), 1.94-2.10 (2H, m), 2.15-2.48 (1H, m), 2.33 (3H, s), 2.53 (1H, dd, J15.2, 10.0 Hz), 2.90 (1H, q, J 6.4 Hz), 3.22 (3H, s), 3.42-3.50 (1H, m),5.02 (1H, d, J 17.5 Hz), 5.29 (1H, d, J 10.7 Hz), 5.85 (1H, d, J 9.9Hz), 6.72 (1H, dd, J 17.5, 10.7 Hz), 7.24 (2H, d, J 8.7 Hz), 7.86 (2H,d, J 8.7 Hz), 8.02 (1H, bs).

Step 3. Mutilin 14-[N-(4-acetoxybenzoyl)carbamate]

The product of Step 2 (570 mg, 1.05 mmol) in dioxane (10 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (56 mg, 11%); ν_(max)(CH₂ Cl₂) 3563, 3419, 2960, 1778, 1761, 1733, 1718, 1604, and 1479 cm⁻¹; ¹ H NMR (CDCl₃) 0.40 (3H, d, J 6.6 Hz), 0.88 (3H, d, J 7.0 Hz),1.10-1.28 (4H, m), 1.38-1.82 (13H, m), 2.12-2.37 (6H, m), 3.37 (1H, dd,J 10.8, 6.6 Hz), 5.24 (1H, dd, J 17.3, 1.4 Hz), 5.38 (1H, dd, J 11.1,1.4 Hz), 5.83 (1H, d, J 8.7 Hz), 6.56 (1H, dd, J 17.4, 11.0 Hz), 7.22(2H, d, J 8.7 Hz), 7.83 (2H, d, J 8.7 Hz), 8.22 (1H, bs); MS (FAB,NOBA/Na) m/z 548 (MNa⁺).

EXAMPLE 38 Mutilin 14-[N-(14-hydroxybenzoyl)carbamate]

The title compound was isolated from the reaction described in Example37, Step 3 (134 mg, 27%); ν_(max) (KBr disc) 1764, 1730, and 1690; ¹ HNMR (CDCl₃ +CD₃ OD) 0.76 (3H, d, J 6.4 Hz), 0.84 (3H, d, J 6.9 Hz),1.05-1.21 (4H, m), 1.37-1.78 (11H, m), 2.00-2.34 (4H, m), 3.32 (1H, d, J6.5 Hz), 5.19 (1H, dd, J 17.4, 1.4 Hz), 5.32 (1H, d, J 11.0 Hz), 5.77(1H, d, J 8.7 Hz), 6.51 (1H, dd, J 17.4, 11.0 Hz), 6.82 (2H, d, J 8.7Hz), 7.66 (2H, d, J 8.7 Hz); MS (FAB, NOBA/Na) m/z 506 (MH⁺) m/z 548(MNa⁺).

EXAMPLE 39 Mutilin 14-[N-(3-methoxybenzoyl)carbamate]

Step 1. 3-Methoxybenzoylisocyanate

Silver cyanate (689 mg, 4.6 mmol) and 3-methoxybenzoylchloride (563 ul,4.0 mmol) in dry dichloromethane (10 ml) were reacted according to themethod described in Example 31, Step 1. The solution containing thetitle compound was immediately used in the next reaction.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-methoxybenzoyl)carbamate]

The solution from Step 1 was cooled to 0° C. and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (336 mg, 1.00 mmol)and the reaction stirred for 1 hour. The title compound was isolated bythe same procedure as described in Example 31, Step 2 (430 mg, 84%);m.p. (CH₂ Cl₂ /hexane) 110-112° C.; ν_(max) (CH₂ Cl₂) 3419, 2931, 1770,1714, 1697, 1601, and 1585 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.89 (3H, d, J 6.9Hz), 1.00 (3H, d, J 6.4 Hz), 1.07-1.56 (12H, m) including 1.20 (3H, s)and 1.32 (3H, s), 1.72 (1H, d, J 15.4 Hz), 1.75 (1H, d, J 11.3 Hz),1.94-2.06 (2H, m), 2.16-2.25 (1H, m), 2.53 (1H, dd, J 15.2, 10.1 Hz),2.90 (1H, q, J 6.5 Hz), 3.23 (3H, s), 3.42-3.50 (1H, m), 3.86 (3H, s),5.01 (1H, d, J 17.4 Hz), 5.30 (1H, d, J 10.8 Hz), 5.85 (1H, d, J 9.9Hz), 6.73 (1H, dd, J 17.5, 10.7 Hz), 7.13 (1H, ddd, J 6.8, 2.6, 1.0 Hz),7.31-7.43 (3H, m), 7.99 (1H, bs); MS (NH₃ DCI) m/z 512 (MH⁺); (Found: C,70.38; H, 8.28; N, 2.91. C₃₀ H₄₁ NO₆ requires C, 70.42; H, 8.08; N,2.74).

Step 3. Mutilin 14-[N-(3-methoxybenzoyl)carbamate]

The product of Step 2 (440 mg, 0.85 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (170 mg, 45%); m.p. (CH₂Cl₂ /hexane) 117° C. (dec.); ν_(max) (CH₂ Cl₂) 3556, 3423, 2961, 1779,1733, and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80 (3H, d, J 6.6 Hz), 0.88 (3H,d, J 6.9 Hz), 1.10-1.81 (16H, m) including 1.23 (3H, s) and 1.52 (3H,s), 2.04-2.37 (4H, m), 3.36 (1H, dd, J 10.9, 6.5 Hz), 3.85 (3H, s), 5.23(1H, dd, J 17.3, 1.5 Hz), 5.37 (1H, dd, J 10.9, 1.4 Hz), 5.83 (1H, d, J8.5 Hz), 6.56 (1H, dd, J 17.3, 10.9 Hz), 7.11 (1H, ddd, J 8.0, 2.4, 1.3Hz), 7.28-7.41 (3H, m), 7.98 (1H, bs); MS (NH₃ DCI) m/z 498 (MH⁺), m/z515 (MNH₄ ⁺).

EXAMPLE 40 Mutilin 14-[N-(2-methoxybenzoyl)carbamate]

Step 1. 2-Methoxybenzoylisocyanate

Silver cyanate (689 mg, 4.6 mmol) and 3-methoxybenzoylchloride (593 ul,4.0 mmol) in dry dichloromethane (10 ml) were reacted according to themethod described in Example 31, Step 1. The solution containing thetitle compound was immediately used in the next reaction; ν_(max) (CH₂Cl₂) 2250 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2-methoxybenzoyl)carbamate]

The solution from Step 1 was cooled to 0° C. and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (336 mg, 1.00 mmol)and the reaction stirred for 1 hour. The title compound was isolated bythe same procedure as described in Example 31, Step 2 (500 mg, 98%);ν_(max) (CH₂ Cl₂) 3344, 2981, 2931, 1772, 1732, 1698, 1602, and 1509cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90 (3H, d, J 6.8 Hz), 1.01 (3H, d, J 6.4 Hz),1.07-1.59 (12H, m) including 1.20 (3H, s) and 1.33 (3H, s), 1.75 (1H, d,J 11.2 Hz), 1.77 (1H, d, J 15.4 Hz), 1.95-2.04 (2H, m), 2.16-2.25 (1H,m), 2.50 (1H, dd, J 15.2, 10.1 Hz), 2.91 (1H, q, J 6.3 Hz), 3.23 (3H,s), 3.44-3.51 (1H, m), 4.04 (3H, s), 5.00 (1H, d, J 17.5 Hz), 5.30 (1H,d, J 10.7 Hz), 5.78 (1H, d, J 9.9 Hz), 6.82 (1H, dd, J 17.5, 10.7 Hz),7.02 (1H, d, J 8.0 Hz), 7.10 (1H, td, J 7.5, 0.7 Hz), 7.54 (1H, td, J7.8, 1.8 Hz), 8.24 (1H, dd, J 7.8, 1.8 Hz), 10.00 (1H, bs); MS (ESI, -veion) m/z 510 (M-H⁻).

Step 3. Mutilin 14-[N-(2-methoxybenzoyl)carbamate]

The product of Step 2 (430 mg, 0.83 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (208 mg, 49%); m.p. (CH₂Cl₂ /hexane) 142-145° C.; ν_(max) (CH₂ Cl₂) 3626, 3563, 3346, 2953,1773, 1733, 1701 and 1609 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.81 (3H, d, J 6.6 Hz),0.88 (3H, d, J 7.0 Hz), 1.15-1.81 (16H, m) including 1.22 (3H, s) and1.52 (3H, s), 2.04-2.38 (4H, m), 3.36 (1H, dd, J 11.1, 6.5 Hz), 4.01(3H, s), 5.23 (1H, dd, J17.3, 1.5 Hz), 5.39 (1H, dd, J 10.9, 1.4 Hz),5.78 (1H, d, J 8.5 Hz), 6.62 (1H, dd, J 17.4, 11.0 Hz), 7.11 (1H, t,J7.6 Hz), 7.52 (1H, td, J 7.8, 1.8 Hz), 8.20 (1H, dd, J 7.8, 1.8 Hz),9.89 (1H, bs); MS (ESI, +ve ion) m/z 520 (MNa⁺).

EXAMPLE 41 Mutilin 14-[N-(phenylacetyl)carbamate]

Step 1. Phenylacetylisocyanate

Silver cyanate (689 mg, 4.6 mmol) and phenylacetylchloride (0.563 ml,4.0 mmol) in dry dichloromethane (10 ml) were reacted according to themethod described in Example 31, Step 1. The solution containing thetitle compound was immediately used in the next reaction.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(phenylacetyl)carbamate]

The solution from Step 1 was cooled to 0C and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (336 mg, 1.00 mmol)and the reaction stirred for 1 hour. The title compound was isolated bythe same procedure as described in Example 31, Step 2 (500 mg, quant.);m.p. (CH₂ Cl₂ /hexane) 187-8° C.; ν_(max) (CH₂ Cl₂) 3383, 2930, 1784,1751, 1698, and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.78 (3H, d, J 6.9 Hz), 1.00(3H, d, J 6.4 Hz), 1.00-1.61 (13H, m), 1.72 (1H, d, J 11.3 Hz),1.92-2.05 (2H, m), 2.14-2.23 (1H, m), 2.46 (1H, dd, J 15.3, 10.1 Hz),2.88 (1H, q, J 6.5 Hz), 3.21 (3H, s), 3.38-3.48 (1H, m), 4.10 (2H, s),5.03 (1H, d, J 17.4 Hz), 5.32 (1H, d, J10.7 Hz), 5.72 (1H, d, J 9.9 Hz),6.63 (1H, dd, J 17.5, 10.7 Hz), 7.24-7.38 (5H, m), 7.50 (1H, bs); MS(NH₃ DCI) m/z 496 (MH⁺), m/z 513 (MNH₄ ⁺).

Step 3. Mutilin 14-[N-(phenylacetyl)carbamate]

The product of Step 2 (460 mg, 0.93 mmol) in dioxane (10 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (202 mg, 45%); m.p. (CH₂Cl₂ /hexane) 187° C.; ν_(max) (CH₂ Cl₂) 3564, 3386, 2941, 1784, 1752,1733, and 1477 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.68 (3H, d, J 6.7 Hz), 0.89 (3H,d, J 7.0 Hz), 1.09-1.82 (15H, m) including 1.22 (3H, s) and 1.40 (3H,s), 2.00-2.38 (5H, m), 3.36 (1H, dd, J 10.4, 6.7 Hz), 4.02 and 4.12 (2H,ABq, J 15.7 Hz), 5.23 (1H, dd, J 17.5, 1.4 Hz), 5.38 (1H, dd, J 10.9,1.3 Hz), 5.71 (1H, d, J 8.4 Hz), 6.57 (1H, dd, J 17.3, 11.1 Hz),7.24-7.35 (5H, m), 7.51 (1H, bs); MS (NH₃ DCI) m/z 482 (MH⁺), m/z 499(MNH₄ ⁺).

EXAMPLE 42 Mutilin 14-[N-(4-carboxybenzoyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-formylbenzoyl)carbamate]

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (680 mg, 2.00 mmol)was combined with 4-formylbenzoyl chloride (1.68 g, 10.0 mmol), silvercyanate (1.50 g, 10.0 mmol) and tetrakis(triphenylphosphine) palladium(0) (25 mg) in dry dichloromethane (25 ml) and the reaction stirred atroom temperature for 6 hours in subdued light and under an atmosphere ofargon. The mixture was filtered through Kieselguhr and the filtratewashed with 1.0M hydrochloric acid followed by water and brine. Afterdrying (MgSO₄) purification was accomplished by chromatography on silicagel, loading in dichloromethane and eluting with mixtures of ethylacetate in hexane. The title compound was isolated as a crystallinesolid (700 mg, 70%); ν_(max) (CH₂ Cl₂) 3406, 2930, 1778, 1707, 1576, and1480 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90 (3H, d, J 6.8 Hz), 1.00 (3H, d, J 6.4Hz), 1.04-1.62 (12H, m), 1.73-1.77 (2H, m), 1.94-2.24 (2H, m), 2.15-2.25(1H, m), 2.54 (1H, dd, J 15.2, 10.0 Hz), 2.88 (1H, q, J 6.3 Hz), 3.22(3H, s), 3.41-3.48 (1H, m), 5.02 (1H, d, J 17.5 Hz), 5.28 (1H, d, J 10.7Hz), 5.85 (1H, d, J 10.0 Hz), 6.67 (1H, dd, J 17.5, 10.0 Hz), 7.95-8.03(5H, m), 8.13 (1H, bs), 10.11 (1H, s); MS (NH₃ DCI) m/z 527 (MNH₄ ⁺).(Found: C, 70.46; H, 8.03; N, 2.55. C₃₀ H₃₉ NO₆ requires C, 70.70; H,7.71; N, 2.75).

Step 2. (3R)-3-Deoxo-11-deoxY-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-carboxybenzoyl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-formylbenzoyl)carbamate] (200 mg, 0.4 mmol) was dissolved inacetone (5 ml) and treated with Jones' reagent (0.05 ml of 8M solutionof [O], 0.4 mmol) and the reaction was stirred at room temperature for 5minutes. More Jones' reagent (0.05 ml) was added and stirring continuedat room temperature. The reaction mixture was treated with isopropanol(1 ml) and then partitioned between ethyl acetate and water. Afterwashing the organic phase with water and brine it was dried (MgSO₄).Removal of solvent in vacuo gave the title compound as a foam (182 mg,87%); ν_(max) (CH₂ Cl₂) 3434, 3273, 2927, 17323, and 1699 cm⁻¹ ; ¹ H NMR(CDCl₃, CD₃ OD)) 0.84 (3H, d, J 6.8 Hz), 0.93 (3H, d, J 6.3 Hz),1.01-1.54 (13H, m), 1.62-1.69 (2H, m), 2.08-2.17 (2H, m), 2.44 (1H, dd,J 15.2, 10.0 Hz 2.85 (1H, q, J 6.3 Hz), 3.16 (3H, s), 3.36-3.41 (1H, m),4.94 (1H, d, J 17.4 Hz), 5.23 (1H, d, J 10.8 Hz), 5.78 (1H, d, J 9.8Hz), 6.65 (1H, dd, J 17.5, 10.7 Hz), 7.84 (2H, d, J 8.5 Hz), 8.05 (2H,d, J 8.5 Hz); MS (NH₃ DCI) m/z 543 (MNH₄ ⁺).

Step 3. Mutilin 14-[N-(4-carboxybenzoyl)carbamate]

The product of Step 2 (600 mg, 1.14 mmol) in dioxane (15 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (3.5 ml), as forExample 1 Step 2, to afford the title compound (280 mg, 68%); ν_(max)(KBr disc) 1766, 1740, and 1709 cm⁻¹ ; ¹ H NMR (d₆ -Acetone) 0.82 (3H,d, J 6.3 Hz), 0.96 (3H, d, J 7.0 Hz), 1.19-1.25 (4H, m), 1.39-1.84 (10H,m), 2.07-2.36 (5H, m), 3.36 (1H, bs, collapse to d in D₂ O, J 6.0 Hz),5.19 (1H, dd, J 11.2, 1.8 Hz), 5.27 (1H, dd, J 17.7, 1.6 Hz), 5.79 (1H,d, J 8.5 Hz), 6.45 (1H, dd, J 17.6, 11.2 Hz), 8.01 (1H, d, J 8.5 Hz),8.14 (1H, d, J 8.1 Hz), 10.04 (1H, s, ex. in D₂ O); MS (ESI, +ve ion)m/z 534 (MNa⁺).

EXAMPLE 43 Mutilin 14-(N-phenoxycarbamate)

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-phenoxycarbamate)

O-Phenylhydroxylamine hydrochloride (165 mg, 1.13 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4epi-mutilin 14-chloroformate(150 mg, 0.38 mmol) and diisopropylethylamine (0.33 ml, 1.9 mmol) indichloromethane (3 ml), as for Example 12 Step 2, to afford the crudetitle compound (150 mg) which was used in the following step withoutpurification; ν_(max) (CH₂ Cl₂) 3368, 1753, 1698 cm⁻¹ ; ¹ H NMR interalia(CDCl₃) 0.87 (3H, d, J 6.9 Hz), 0.98 (3H, d, J 6.4 Hz) 1.13 (3H, s),1.20 (3H, s), 1.05-1.30 (4H, m), 1.52 (2H, m), 1.69 (1H, d, J 15.4 Hz),1.71 (1H, d, J 11.2 Hz), 1.98 (2H, m), 2.18 (1H, m), 2.48 (1H, dd, J15.3. 10.1 Hz), 2.88 (1H, q, J 6.4 Hz), 3.20 (3H, s), 3.44 (1H, m), 5.01(1H, d, 17.5 Hz), 5.28 (1H, d, J 10.6 Hz), 5.76 (1H, d, J 10.0 Hz), 6.69(1H, dd, J 17.4, 10.6 Hz), 7.08 (3H, m), 7.63 (1H, s); MS(CI) m/z 487(MNH₄ ⁺).

Step 2. Mutilin 14-(N-phenoxycarbamate)

The product of Step 1 (112 mg) in dioxane (3 ml) was treated with asaturated solution of zinc chloride in conc. HCl (1 ml), as for Example1 Step 2, to afford the title compound (11.5 mg,); ν_(max) (CH₂ Cl₂)3562, 1735 cm⁻¹, ¹ H NMR (CDCl₃) 0.68 (3H,br ), 0.86 (3H, d, J 6.9 Hz),1.06-1.79 (9H, m), 1.16 (3H, s), 1.29 (3H, s), 2.05 (2H, m), 2.23 (3H,m), 3.33 (1H, m,), 5.21 (1H, dd, J 17.2, 1.3 Hz), 5.36 (1H, d, J 11.1Hz), 5.75 (1H, d, J 8.3 Hz), 6.46 (1H, dd, J 17.3, 11.0 Hz), 6.91 (1H,d, J 7.9 Hz), 7.06 (1H, t, J 7.3 Hz), 7.28 (2H, m); MS(EI) m/z 456 (M⁺)Found: 455.2677, C₂₇ H₃₇ NO₅ requires 455.2672.

EXAMPLE 44 Mutilin 14-[N-(4-trifluoromethylbenzoyl)carbamate]

Step 1. 4-Trifluoromethylbenzoylisocyanate

Silver cyanate (690 mg, 4.6 mmol) and 4-trifluoromethylbenzoylchloride(0.6 ml, 4.0 mmol) in dry dichloromethane (5 ml) were reacted accordingto the method described in Example 31, Step 1. The solution containingthe title compound was immediately used in the next reaction; ν_(max)(CH₂ Cl₂) 2246 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-trifluoromethylbenzoyl)carbamate]

The solution from step 1 was treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.00 mmol)and the reaction stirred for 1.5 hour. The title compound was isolatedby the same procedure as described in Example 31, Step 2 (405 mg, 74%);ν_(max) (CH₂ Cl₂) 3416, 1780, 1718, 1698 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.85(1H, m), 0.90 (3H, d, J 6.9 Hz), 1.01 (3H, d, J 6.4 Hz), 1.08-1.31 (3H,m), 1.21 (3H, s), 1.31 (3H, s), 1.52 (2H, m), 1.74 (2H, m), 2.03 (2H,m), 2.21 (1H, m), 2.54 (1H, dd, J 15.2, 10.1 Hz), 2.89 (1H, q, J 6.4Hz), 3.23 (3H, s), 3.46 (1H, m), 5.02 (1H, d, J 17.4 Hz), 5.30 (1H, d, J10.6 Hz), 5.85 (1H, d, J 10.0 Hz), 6.68 (1H, dd, J 17.4, 10.6 Hz), 7.77(1H, d, J 8.3 Hz), 7.94 (1H, d, J 8.2 Hz), 8.02 (1H, s); MS (EI) m/z 549(M⁺) Found: 549.2703, C₃₀ H₃₈ F₃ NO₅ requires 549.2702.

Step 3. Mutilin 14-[N-(4-trifluoromethylbenzoyl)carbamate]

The product of Step 2 (385 mg, 0.7 mmol) in dioxane (6 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (148 mg, 40%); ν_(max)(CH₂ Cl₂) 3421, 1781, 1734 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80 (3H, d, J 6.7Hz), 0.89 (3H, d, J 7.0 Hz), 1.18 (1H, m) 1.20 (3H, s) 1.51 (3H, s),1.41-1.82 (8H, m), 2.04-2.36 (5H, m), 3.37 (1H, dd, J 10.7, 6.6 Hz),5.24 (1H, dd, J 17.4, 1.4 Hz), 5.37 (1H, dd, J 11.0, 1.3 Hz), 5.82 (1H,d, J 8.5 Hz), 6.53 (1H, dd, J 17.3, 11 Hz), 7.75 (2H, d, J 8.3 Hz), 7.90(1H, d, J 8.2 Hz), 7.98 (1H, bs); MS (CI) m/z 553 (MNH₄ ⁺).

EXAMPLE 45 Mutilin 14-[N-(3-trifluoromethylbenzoyl)carbamate]

Step 1. 3-Trifluoromethylbenzoylisocyanate

Silver cyanate (690 mg, 4.6 mmol) and 3-trifluoromethylbenzoylchloride(0.6 ml, 3.98 mmol) in dry dichloromethane (5 ml) were reacted accordingto the method described in Example 31, Step 1. The solution containingthe title compound was immediately used in the next reaction; ν_(max)(CH₂ Cl₂) 2250 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-trifluoromethylbenzoyl)carbamate]

The solution from step 1 was treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 1.5 hour. The title compound was isolatedby the same procedure as described in Example 31, Step 2 (480 mg, 87%);ν_(max) (CH₂ Cl₂) 3414, 1780, 1718, 1698 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90(3H, d, J 6.8 Hz), 1.00 (3H, d, J 6.4 Hz), 1.05-1.43 (4H, m), 1.21 (3H,s), 1.30 (3H, s), 1.53 (2H, m), 1.71 (1H, d, J 15.3 Hz), 1.75 (1H, d, J11.2 Hz), 2.00 (2H, m), 2.20 (1H, m), 2.55 (1H, dd, J 15.2, 10.1 Hz),2.89 (1H, q, J 6.4 Hz), 3.22 (3H, s), 3.46 (1H, ddd, J 11.2, 5.3, 2.9Hz), 5.02 (1H, d, J 17.5 Hz), 5.28 (1H, d, J 10.7 Hz), 5.86 (1H, d, J10.0 Hz), 6.67 (1H, dd, J 17.5, 10.7 Hz), 7.65 (1H, t, J 7.8 Hz), 7.86(1H, d, J 7.9 Hz), 8.01 (1H, d, J 7.9 Hz), 8.09 (2H, brs); MS (CI) m/z567 (MNH₄ ⁺) (Found: C, 65.50; H, 6.90; N, 2.71. C₃₀ H₃₈ F₃ NO₅ requiresC, 65.56; H, 6.97; N, 2.55).

Step 3. Mutilin 14-[N-(3-trifluoromethylbenzoyl)carbamate]

The product of Step 2 (350 mg, 0.64 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (184 mg, 54%); ν_(max)(CH₂ Cl₂) 3411, 1781, 1734 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80 (3H, d, J 6.7Hz), 0.89 (3H, d, J 6.9 Hz), 1.15 (1H, m) 1.20 (3H, s) 1.51 (3H, s),1.41-1.81 (8H, m), 2.11-2.35 (5H, m), 3.37 (1H, dd, J 10.9, 6.6 Hz),5.23 (1H, dd, J 17.3, 1.4 Hz), 5.35 (1H, dd, J 11.0, 1.3 Hz), 5.82 (1H,d, J 8.5 Hz), 6.52 (1H, dd, J 17.3, 11.0 Hz), 7.63 (1H, t, J 7.8 Hz),7.84 (1H, d, J 7.8 Hz), 7.98 (1H, d, J 7.8 Hz) 8.06 (1H, s), 8.12 (1H,s); MS (Electrospray) m/z 558 (MNa⁺).

EXAMPLE 46 Mutilin 14-[N-(2-trifluoromethylbenzoyl)carbamate]

Step 1. 2-Trifluoromethylbenzoylisocyanate

Silver cyanate (690 mg, 4.6 mmol) and 2-trifluoromethylbenzoylchloride(0.5 ml, 3.4 mmol) in dry dichloromethane (5 ml) were reacted accordingto the method described in Example 31, Step 1 for 3 hours. The solutioncontaining the title compound was immediately used in the next reaction;ν_(max) (CH₂ Cl₂) 2254 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2-trifluoromethylbenzoyl)carbamate]

The solution from step 1 was treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 0.5 hour. The title compound was isolatedby the same procedure as described in Example 31, Step 2(231mg, 42%);ν_(max) (CH₂ Cl₂) 3384, 1782, 1760, 1698 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.85(3H, d, J 6.8 Hz), 0.95 (3H, d, J 6.4 Hz), 1.05-1.36 (4H, m), 1.19 (6H,s), 1.50 (2H, m), 1.62 (1H, d, J 15.4 Hz), 1.71 (1H, d, J 11.3 Hz), 1.98(2H m), 2.17 (1H, m), 2.48 (1H, dd, J 15.3, 10.1 Hz), 2.81 (1H, q, J 6.4Hz), 3.21 (3H s), 3.43 (1H, m), 4.98 (1H, d, J 17.5 Hz), 5.23 (1H, d, J10.7 Hz), 5.72 (1H, d, J 10.0 Hz), 6.50 (1H, dd, J 17.4, 10.6 Hz), 7.50(1H, m,), 7.64 (2H, m), 7.76 (2H, m); MS (CI) m/z 567 (MNH₄ ⁺).

Step 3. Mutilin 14-[N-(2-trifluoromethylbenzoyl)carbamate]

The product of Step 2 (207 mg, 0.38 mmol) in dioxane (3 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (149 mg, 74%); ν_(max)(CH₂ Cl₂) 3390, 1784, 1763, 1734, 1705 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.76 (3H,d, J 6.9 Hz), 0.83 (3H, d, J 7.0 Hz), 1.16 (1H, m) 1.18 (3H, s) 1.38(3H, s), 1.36-1.49 (4H, m), 1.55-1.76 (4H, m), 2.04-2.28 (5H, m), 3.33(1H, dd, J 10.6, 6.7 Hz), 5.19 (1H, dd, J 17.3, 1.3 Hz), 5.28 (1H, d, J11.0 Hz), 5.67 (1H, d, J 8.4 Hz), 6.36 (1H, dd, J 17.2, 11.0 Hz), 7.44(1H, m), 7.62 (2H, m), 7.72 (2H, m); MS (CI) m/z 553 (MNH₄ ⁺).

EXAMPLE 47 Mutilin 14-[N-iso-nicotinoylcarbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-iso-nicotinoylcarbamate]

A mixture of silver cyanate (690 mg, 4.6 mmol), iso-nicotinoyl chloridehydrochloride (535 mg, 3.0 mmol), tetrakis triphenylphosphine palladium(0) (18.5 mg, 0.016 mmol) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)in dichloromethane (15 ml) was protected from light and stirred at roomtemperature under argon for 66 hour. Diisopropylethylamine (1 ml) wasthen added and the reaction mixture filtered through Kieselguhr.Concentration afforded a crude product which was purified by silica gelchromatography eluting with 50-75% ethyl acetate/hexane mixtures to givethe title compound (212 mg, 44%); ν_(max) (CH₂ Cl₂) 3406, 1781, 1721,1698 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.89 (3H, d, J 6.9 Hz), 1.01 (3H, d, J 6.4Hz), 1.03-1.62 (6H, m), 1.21 (3H, s), 1.31 (3H, s), 1.70 (1H, d, J 15.5Hz), 1.75 (1H, d, J 11.5 Hz) 2.00 (2H, m), 2.21 (1H, m), 2.54 (1H, dd, J15.2, 10.1 Hz), 2.88 (1H, q, J 6.3 Hz) 3.22 (3H, s), 3.46 (1H, ddd, J11.2, 8.3, 5.3 Hz), 5.02 (1H, d, J 17.5 Hz), 5.29 (1H, d, J 10.7 Hz),5.85 (1H, d, J 10.0 Hz), 6.66 (1H, dd, J 17.5, 10.7 Hz), 7.64 (2H, dd, J4.4, 1.6 Hz), 8.11 (1H, s), 8.84 (2H, dd, J 4.4, 1.5 Hz); MS (CI) m/z483 (MNH₄ ⁺).

Step 2. Mutilin 14-[N-iso-nicotinoylcarbamate]

The product of Step 1 (177 mg, 0.37 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (29.6 mg, 17%); ν_(max)(CH₂ Cl₂) 3400, 1783, 1734 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.79 (3H, d, J 6.8Hz), 0.89 (3H, d, J 7.0 Hz), 1.16 (1H, m) 1.20 (3H, s) 1.50 (3H, s),1.44-1.82 (8H, m), 2.11-2.35 (5H, m), 3.37 (1H, dd, J 10.7, 6.6 Hz),5.23 (1H, dd, J 17.3, 1.4 Hz), 5.36 (1H, dd, J 10.9, 1.3 Hz), 5.82 (1H,d, J 8.5 Hz), 6.51 (1H, dd, J 17.3, 11.0 Hz), 7.62 (1H, dd, J 4.5, 1.5Hz), 8.20 (1H, s), 8.79 (2H, dd, J 4.5, 1.7 Hz); MS (CI) m/z 469 (MH⁺).

EXAMPLE 48 Mutilin 14-[N-nicotinoylcarbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-nicotinoylcarbamate]

A mixture of silver cyanate (690 mg, 4.6 mmol), nicotinoyl chloridehydrochloride (712 mg, 4.0 mmol), tetrakis tripheylphosphine palladium(0) (14 mg, 0.012 mmol), diisopropylethylamine (0.7 ml, 4.0 mmol) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)in dichloromethane (14 ml) was protected from light and stirred atreflux under argon for 50 minutes. The reaction mixture was filteredthrough Kieselguhr and concentrated, to afforded a crude product whichwas purified by silica gel chromatography to give the title compound(177 mg, 37%); ν_(max) (CH₂ Cl₂) 3410, 1779, 1717, 1698 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.90 (3H, d, J 6.8 Hz), 1.00 (3H, d, J 6.4 Hz), 1.08-1.56 (6H,m), 1.21 (3H, s), 1.30 (3H, s), 1.71 (1H, d, J 15.3 Hz), 1.75 (1H, d, J11.2 Hz), 2.00 (2H, m), 2.21 (1H, m), 2.54 (1H, dd, J 15.3, 10.1 Hz),2.89 (1H, q, J 6.4 Hz), 3.22 (3H, s), 3.46 (1H, ddd, J 11.2, 8.1, 5.4Hz), 5.02 (1H, d, J 17.4 Hz), 5.28 (1H, d, J 10.7 Hz), 5.85 (1H, d, J10.0 Hz), 6.67 (1H, dd, J 17.5, 10.7 Hz), 7.46 (1H, dd, J 7.6, 4.9 Hz),8.16 (2H, m), 8.81 (1H, dd, J 4.9, 1.5 Hz) 9.02 (1H, d, J 2.3 Hz); MS(CI) m/z 483 (MNH₄ ⁺).

Step 2. Mutilin 14-[N-nicotinoylcarbamate]

The product of Step 1 (153 mg, 0.32 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (95 mg, 64%); ν_(max)(CH₂ Cl₂) 3410, 1781, 1734cm⁻¹ ; ¹ H NMR (CDCl₃) 0.81 (3H, d, J 6.7 Hz),0.89 (3H, d, J 6.9 Hz), 1.18 (1H, m) 1.20 (3H, s) 1.50 (3H, s),1.44-1.82 (8H, m), 2.11-2.35 (5H, m), 3.37 (1H, dd, J 10.6, 6.7 Hz),5.23 (1H, d, J 17.4 Hz), 5.36 (1H, d, J 11.1 Hz), 5.82 (1H, d, J 8.4Hz), 6.52 (1H, dd, J 17.3, 11.0 Hz), 7.44 (1H, dd, J 7.8, 4.9 Hz), 8.12(2H, br), 8.80 (1H, d, J 3.4 Hz), 8.99 (1H, d, J 1.7 Hz); MS (EI) m/z469 (MH⁺), Found: 469.2704, C₂₇ H₃₇ N₂ O₅ (MH⁺) requires 469.2702.

EXAMPLE 49 Mutilin 14-[N-2-furoylcarbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-2-furoylcarbamate]

A mixture of silver cyanate (690 mg, 4.6 mmol), 2-furoyl chloride (0.4ml, 3.0 mmol), tetrakis tripheylphosphine palladium (0) (17 mg, 0.015mmol)and (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg,1.0 mmol) in 1,2-dichloroethane (10 ml) was protected from light andstirred at room temperature under argon for 41 hour. The reactionmixture was filtered through Kieselguhr and concentrated, to afforded acrude product, which was purified by silica gel chromatography to givethe title compound (468 mg, 99%); ν_(max) (CH₂ Cl₂) 3415, 1777, 1714,1699 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.89 (3H, d, J 6.9 Hz), 1.00 (3H, d, J 6.4Hz), 1.07-1.42 (4H, m), 1.20 (3H, s), 1.33 (3H, s), 1.53 (2H, m), 1.71(1H, d, J 15.3 Hz), 1.75 (1H, d, J 11.3 Hz), 2.02 (2H, m), 2.20 (1H, m),2.53 (1H,dd,J 15.4, 10.1 Hz), 2.90 (1H, q, J 6.4 Hz), 3.23 (3H, s), 3.47(1H, ddd, J 11.2, 8.3, 5.3 Hz), 5.01 (1H, d, J 17.4 Hz), 5.30 (1H, d, J10.7 Hz), 5.84 (1H, d, J 9.9 Hz), 6.59 (1H, dd, J 3.5, 1.7 Hz), 6.73(1H, dd, J 17.4, 10.6 Hz), 7.34 (1H, d, J 3.3 Hz), 7.54 (1H, s), 8.20(1H, s); MS (CI) m/z 471 (M⁺).

Step 2. Mutilin 14-[N-2-furoylcarbamate]

The product of Step 2 (200 mg, 0.42 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (129 mg, 67%); ν_(max)(CH₂ Cl₂) 3412, 1777, 1733, 1716 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80 (3H, d, J6.7 Hz), 0.89 (3H, d, J 7.0 Hz), 1.18 (1H, m) 1.19 (3H, s) 1.54 (3H, s),1.37-1.82 (8H, m), 2.10-2.38 (5H, m), 3.37 (1H, dd, J 11.0, 6.6 Hz),5.23 (1H, dd, J 17.3, 1.5 Hz), 5.38 (1H, dd, J 11.0, 1.5 Hz), 5.83 (1H,d, J 8.5 Hz), 6.56 (1H, dd, J 17.3, 11.0 Hz), 6.57 (1H, dd, J 3.5, 1.8Hz), 7.32 (1H, d, J 3.3 Hz), 7.52 (1H, d, J 2.1 Hz), 8.15 (1H, s); MS(CI) m/z 475 (MNH₄ ⁺).

EXAMPLE 50 Mutilin 14-[N-acetylcarbamate]

Step 1. Acetyl Isocyanate

Silver cyanate (690 mg, 4.6 mmol) and acetyl chloride (0.28 ml, 3.94mmol) in dry dichloromethane (5 ml) were reacted according to the methoddescribed in Example 31, Step 1 for 1.75 hours. The solution containingthe title compound was immediately used in the next reaction; ν_(max)(CH₂ Cl₂) 2257 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-acetylcarbamate]

The solution from step 1 was treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 10 minutes. The title compound was isolatedby the same procedure as described in Example 31, Step 2 (420 mg, 100%);ν_(max) (CH₂ Cl₂) 3388, 1753, 1713 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.83 (3H, d, J6.9 Hz), 1.00 (3H, d, J 6.4 Hz), 1.07-1.54 (6H, m), 1.21 (6H, s), 1.62(1H, d, J 15.7 Hz), 1.73 (1H, d, J 11.3 Hz), 1.99 (2H, m), 2.20 (1H, m),2.48 (3H, s), 2.49 (1H, dd, J 15.4, 10.0 Hz), 2.88 (1H, q, J 6.4 Hz),3.22 (3H, s), 3.45 (1H, ddd, J 11.2, 8.1, 5.3 Hz), 5.03 (1H, d, J 1 17.5Hz), 5.33 (1H, d, J 10.7 Hz), 5.72 (1H, d, J 10.0 Hz), 6.63 (1H, dd, J17.5, 10.7 Hz), 7.45 (1H, s); MS (EI) m/z 419 (M⁺), Found: 419.2674, C₂₄H₃₇ NO₅ requires 419.2672.

Step 3. Mutilin 14-[N-acetylcarbamate]

The product of Step 2 (284 mg, 0.68 mmol) in dioxane (3 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (190 mg, 69%); ν_(max)(CH₂ Cl₂) 3392, 1755, 1734, 1714 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.74 (3H, d, J6.7 Hz), 0.89 (3H, d, J 7.0 Hz), 1.16 (1H, m) 1.19 (3H, s) 1.43 (3H, s),1.37-1.55 (5H, m),1.59-1.85 (3H, m), 2.05-2.38 (5H, m), 2.42 (3H, s),3.37 (1H, dd, J 10.6, 6.6 Hz), 5.23 (1H, dd, J 17.4, 1.3 Hz), 5.37 (1H,dd, J 11.0, 1.3 Hz), 5.72 (1H, d, J 8.4 Hz), 6.49 (1H, dd, J 17.4, 11.0Hz), 7.51 (1H, s); MS (CI) m/z 423 (MNH₄ ⁺).

EXAMPLE 51 Mutilin 14-[N-(4-chlorobenzenesulphonyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(500 mg) in dry dichloromethane (7 ml) was treated with4-chlorobenzenesulphonamide (265 mg), diisopropylethylamine (0.5 ml),and 4-dimethylaminopyridine (10 mg), and the solution was stirred for 30minutes at room temperature. The solution was diluted with ethyl acetate(50 ml) and washed with dilute HCl (30 ml), water (30 ml), and saturatedbrine (30 ml). The solution was dried (sodium sulphate) and the solventwas removed by evaporation under reduced pressure to yield a white foam(780 mg).

The foam was dissolved in 1,4-dioxane (8 ml) and treated with asaturated solution of zinc chloride in conc. HCl (2.5 ml). The solutionwas stirred for 2.5 hours at room temperature, and was then diluted withethyl acetate (50 ml) and washed three times with water. The solutionwas dried (sodium sulphate) and the solvent was removed by evaporationunder reduced pressure to yield a pink foam. Crystallisation fromdichloromethane--hexane gave the title compound as colourless crystals(555 mg), m.p. 216-218° C.; λ_(max) (EtOH) 230 nm (ε 12,100); ν_(max)(CHCl₃) 3380, 1735, and 1210 cm⁻¹ ; δ_(H) (CDCl₃) 7.94 (2H, d, J 5 Hz),7.52 (2H, d, J 5 Hz), 6.27 (1H, dd, J 17.4 and 11 Hz), 5.61 (1H, d, J8.4 Hz), 5.24 (1H, dd, J 11 and 1.2 Hz), 5.10 (1H, dd, J 17.4 and 1.2Hz), 3.30 (1H, dd, J 10.1 and 6.7), 2.20 (3H, m), 1.95 (2H, m), 1.8-1.0(overlapping multiplets), 1.34 (3H, s), 1.09 (3H, s), 0.83 (3H, d, J 7Hz), and 0.52 (3H, d, J 6.8 Hz); MS (CI) m/z 555 (M.NH₄ ⁺).

EXAMPLE 52 Mutilin 14-[N-(4-fluorobenzenesulphonyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-fluorobenzenesulphonyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(200 mg) in dry dichloromethane (3 ml) was treated with4-fluorobenzenesulphonamide (180 mg), diisopropylethylamine (0.2 ml),and 4-dimethylaminopyridine (2 mg), and the solution was stirred for 30minutes at room temperature. The solution was diluted with ethyl acetate(50 ml) and washed with dilute HCl (20 ml), water (20 ml), and saturatedbrine (20 ml). The solution was dried (sodium sulphate) and the solventwas removed by evaporation under reduced pressure to yield a colourlessgum. Chromatography on silica gel using ethyl acetate--hexane gave thetitle compound as a colourless gum (240 mg); ν_(max) (CHCl₃) 3379, 1737,1697, and 1594 cm⁻¹ ; MS (EI) m/z 535 (M⁺) (Found: M⁺, 535.2408. C₂₈ H₃₈NO₆ FS requires M, 535.2404).

Step 2. Mutilin 14-[N-(4-fluorobenzenesulphonyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-fluorobenzenesulphonyl)]-carbamate (200 mg) in 1,4-dioxane (4ml) was treated with a saturated solution of zinc chloride in conc. HCl(1.5 ml) and the solution was kept at room temperature for 1.5 hours.The solution was diluted with ethyl acetate (50 ml) and was washed threetimes with water (20 ml portions). The solution was dried (sodiumsulphate) and the solvent was removed by evaporation under reducedpressure to give a colourless gum. Chromatography on silica gel usingethyl acetate--hexane gave the title compound as colourless crystals(140 mg). Recrystallisation from dichloromethane--hexane gave colourlessneedles, m.p. 228-229° C.; λ_(max) (EtOH) 217 nm (ε 11,660); δ_(H)(CDCl₃) 8.01 (2H, dd, J 9 and 5 Hz), 7.20 (2H, t, J 9 Hz), 6.27 (1H, dd,J 17.5 and 11 Hz), 5.58 (1H, d, J 8.3 Hz), 5.20 (1H, dd, J 11 and 1.2Hz), 5.06 (1H, dd, J 17.5 and 1.2 Hz), 3.20 (1H, d, J 6.2 Hz), 2.22 (2H,m), 1.97 (2H, m), 1,8-1.0 (overlapping multiplets), 1.35 (3H, s), 1.09(3H, s), 0.85 (3H, d, J 7 Hz), 0.51 (3H, d, J 6.7 Hz); MS (CI) m/z 539(M.NH₄ ⁺).

EXAMPLE 53 Mutilin 14-[N-(4-n-propylbenzenesulphonyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-n-propylbenzenesulphonyl)]-carbamate

Using the process described in Example 52, Step 1, (3R)-3-deoxo-11-deoxymethoxy-11-oxo-4-epi-mutilin 14-chloroformate (200 mg) and4-n-propylbenzenesulphonamide (150 mg) were converted into the titlecompound, which was obtain as a colour gum (220mg); MS (CI) m/z 577(M.NH₄.sup.).

Step 2. Mutilin 14-[N-(4-n-propylbenzenesulphonyl)]-carbamate

Using the process described in Example 52, Step 2,(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-n-propylbenzenesulphonyl)]-carbamate (190 mg) was convertedinto the title compound, which was obtained as a colourless gum (150mg); ν_(max) (CHCl₃) 3565, 3384, 1735, 1598, and 1421 cm⁻¹ ; δ_(H)(CDCl₃) 7.85 (2H, d, J 8.5 Hz), 7.32 (2H, d, J 8.5 Hz), 6.28 (1H, dd, J17.3 and 11 Hz), 5.61 (1H, d, J 8.3 Hz), 5.23 (1H, dd, J 11 and 1.3 Hz),5.08 (1H, dd, J 17 and 1.3 Hz), 3.29 (1H, dd, J 10.2 and 6.6 Hz), 2,67(2H, t, J 7.3 Hz), 2.20 (2H, m), 1.95 (2H, m), 1.8-0.8 (overlappingmultiplets), 0.49 (3H, d, J 6.7 Hz); MS (CI) m/z 563 (M.NH₄ ⁺).

EXAMPLE 54 Mutilin 14-[N-(4-hydroxybenzenesulphonyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 1 4-chloroformate(300 mg) in dry dichloromethane (5 ml) was treated with4-hydroxybenzenesulphonamide (170 mg), diisopropylethylamine (0.35 ml),and 4-dimethylaminopyridine (8 mg), and the solution was stirred for 30minutes at room temperature. The solution was diluted with ethyl acetate(50 ml) and washed with dilute HCl (20 ml), water (20 ml), and saturatedbrine (20 ml). The solution was dried (solium sulphate) and the solventwas removed by evaporation under reduced pressure to yield a colourlessgum. Chromatography on silica gel using ethyl acetate-hexane gave theproduct as a white foam (410 mg).

The above product was dissolved in 1,4-dioxane (8 ml) and the solutionwas treated with a saturated solution of zinc chloride in conc. HCl (3ml); the solution was kept at room temperature for 3.5 hours. Thesolution was diluted with ethyl acetate (50 ml) and was washed threetimes with water (20 ml portions). The solution was dried (sodiumsulphate) and the solvent was removed by evaporation under reducedpressure to give a pale yellow gum. Chromatography on silica gel usingethyl acetate-hexane gave the product as a white foam (180 mg). The NMRspectrum of this product showed that it contained two different mutilinmoieties, and suggested that it had been derived by simultaneousreaction of 4-epi-mutilin chloroformate molecules with both the hydroxyland the sulphonamido groups of 4-hydroxybenzenesulphonamide:

    [mutilin]-O.sub.2 CO.C.sub.6 H.sub.4.SO.sub.2 NHCO.sub.2 -[mutilin]

The above product was dissolved in methanol (8 ml) and the solution wastreated with 1M NaOH (1 ml) and kept at room temperature for 6 hours.The solution was diluted with ethyl acetate (50 ml) and was washed withdilute HCl (20 ml) and saturated brine (20 ml). The solution was dried(sodium sulphate) and the solvent was removed by evaporation underreduced pressure to give a yellow gum. Chromatography on silica gelusing ethyl acetate--hexane gave the title compound as a white solid(107 mg); λ_(max) (EtOH) 239 nm (ε 12,340); ν_(max) (CHCl₃) 3690, 3583,3382, 1734, 1602, 1418, and 1157 cm⁻¹ ; δ_(H) (CDCl₃ -d₄ -MeOH) 7.77(2H, d, J 7 Hz), 6.84 (2H, d, J 7 Hz), 6.28 (1H, dd, J 17.3 and 11 Hz),5.56 (1H, d, J 8.3 Hz), 5.21 (1H, d, J 11 Hz), 5.07 (1H, d, J 17.3 Hz),3.26 (1H, d, J 6.4 Hz), 2.5-1.0 (overlapping multiplets), 0.82 (3H, d, J7 Hz), 0.51 (3H, d, J 6.5 Hz); MS (CI) m/z 537 (M.NH₄ ⁺), 519. (M⁺).

EXAMPLE 55 Mutilin 14-[N-(3,4-dimethoxybenzoyl)carbamate]

Step 1. 3,4-Dimethoxybenzoylisocyanate

Silver cyanate (690 mg, 4.6 mmol) and 3,4-dimethoxybenzoylchloride (800mg, 4.0 mmol) in dry dichloromethane (5 ml) were reacted according tothe method described in Example 31, Step 1. The solution containing thetitle compound was immediately used in the next reaction; ν_(max) (CH₂Cl₂) 2238 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3,4-dimethoxybenzoyl)carbamate]

The solution from step 1 was treated with(3R)-3-deoxo-11-deoxo-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 40 minutes. The title compound was isolatedby the same procedure as described in Example 31, Step 2 (392 mg, 72%);ν_(max) (CH₂ Cl₂) 3430, 1774, 1698 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.91 (3H, d, J6.8 Hz), 1.00 (3H, d, J 6.4 Hz), 1.05-1.57 (6H, m), 1.21 (3H, s), 1.34(3H, s), 1.73 (1H, d, J 15.3 Hz), 1.75 (1H, d, J 10.5 Hz), 2.02 (2H, m),2.20 (1H, m), 2.54 (1H, dd, J 15.2, 10.1 Hz), 2.91 (1H, q, J 6.2 Hz),3.23 (3H, s), 3.47 (1H, m), 3.95 (6H, s), 5.02 (1H, d, J 10.7 Hz), 5.85(1H, d, J 9.9 Hz), 6.79 (1H, dd, J 17.5 Hz), 6.90 (1H, d, J 8.4 Hz),7.34 (1H, dd, J 8.4, 2.0 Hz), 7.46 (1H, d, J 2.0 Hz), 7.94 (1H, s); MS(CI) m/z 542 (MH⁺).

Step 3. Mutilin 14-[N-(3,4-dimethoxybenzoyl)carbamate]

The product of Step 2 (275 mg, 0.51 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (75 mg, 28%); ν_(max)(KBr disc) 3305, 1768, 1730, 1687 cm⁻ ; ¹ H NMR (CDCl₃) 0.82 (3H, d, J6.6 Hz), 0.89 (3H, d, J 6.9 Hz), 1.20 (1H, m), 1.23 (3H, s), 1.54 (3H,s), 1.44-1.82 (8H, m), 2.12-2.38 (5H, m), 3.38 (1H, dd, J 10.7, 6.6 Hz),3.94 (6H, s), 5.24 (1H, dd, J 17.4, 1.4 Hz), 5.38 (1H, dd, J 10.9, 1.4Hz), 5.84 (1H, d, J 8.5 Hz), 6.58 (1H, dd, J 17.3, 11.0 Hz), 6.88 (1H,d, J 8.4 Hz), 7.30 (1H, dd, J 8.4, 2.0 Hz), 7.43 (1H, d, J 2.1 Hz), 7.86(1H, s); MS (EI) m/z 527 (M⁺), Found: 527.2884, C₃₀ H₄₁ NO₇ requires527.2883.

EXAMPLE 56 Mutilin 14-[N-3,4-methylenedioxybenzoyl)carbamate]

Step 1. 3,4-Methylenedioxybenzoylisocyanate

Silver cyanate (690 mg, 4.6 mmol) and piperonyloyl chloride (738 mg, 4.0mmol) in dry dichloromethane (5 ml) were reacted according to the methoddescribed in Example 31, Step 1. The solution containing the titlecompound was immediately used in the next reaction; ν_(max) (CH₂ Cl₂)2238 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3,4-methylenedioxybenzoyl)carbamate]

The solution from step 1 was treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1.0 mmol)and the reaction stirred for 40 minutes. The title compound was isolatedby the same procedures as described in Example 31, Step 2 (283 mg, 54%);ν_(max) (CH₂ Cl₂) 3428, 1775, 1698 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90 (3H, d, J6.9 Hz), 1.00 (3H, d, J 6.4 Hz), 1.07-1.56 (6H, m), 1.20 (3H, s), 1.31(3H, s), 1.71 (1H, d,J 15.3 Hz), 1.75 (1H, d,J 11.2 Hz), 1.99 (2H, m),2.20 (1H, m), 2.52 (1H, dd, J 15.2, 1 0.1 Hz), 2.90 (1H, q, J 6.5 Hz),3.23 (3H, s), 3.46 (1H, ddd, J 11.2, 8.2, 5.3 Hz), 5.01 (1H, d, J 17.4Hz), 5.29 (1H, d, J 10.7 Hz), 5.84 (1H, d, J 10.0 Hz), 6.07 (2H, s),6.72 (1H, dd, J 17.5, 10.7 Hz), 6.87 (1H, d, J 8.0 Hz), 7.32 (1H, d, J1.5 Hz), 7.36 (1H, dd, J 7.9, 1.8 Hz), 7.89 (1H, s); MS (CI) m/z 543(MNH₄ ⁺), 526 (MH⁺).

Step 3. Mutilin 14-[N-(3,4-methylenedioxybenzoyl)carbamate]

The product of Step 2 (237 mg, 0.45 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml), as forExample 1 Step 2, to afford the title compound (151 mg, 65%); ν_(max)(CH₂ Cl₂) 3432, 1777, 1733, 1712 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80 (3H, d, J6.6 Hz), 0.89 (3H, d, J 7.0 Hz), 1.18 (1, m), 1.19 (3H,s), 1.38-1.83(8H, m), 1.5 (3H,s), 2.09-2.37 (5H, m), 3.37 (1H, dd, J 10.9, 6.6 Hz),5.23 (1H, dd J 17.4, 1.5 Hz), 5.38 (1H, dd, J 11.0 1.5 Hz), 5.82 (1H, d,J 8.5 Hz), 6.06 (2H, s), 6.56 (1H, dd, J 17.4, 11.0 Hz), 6.85 (1H, d, J8.0 Hz), 7.29 (1H, d, J 1.6 Hz), 7.32 (1H, dd, J 8.1, 1.8 Hz), 7.81 1H,s); MS (EI) m/z 511 (M⁺), Found: 511.2566, C₂₉ H₃₇ NO₇ requires511.2570.

EXAMPLE 57 Mutilin 14-(N-p-methoxysulphonylcarbamate)

Step 1. Mutilin 11-dichloroacetate

Mutilin (1.0 g, 3.12 mmol) was disolved in dry THF (10 ml) under argonand treated with pyridine (0.33 ml, 4.06 mmol), dichloroacetic anhydride(820 mg, 3.42 mmol) in THF (2 ml), and N,N-4-dimethylaminopyridine (5mg). After 24 hours the reaction was diluted with ethyl acetate, washedwith 1M hydrochloric acid, saturated sodium hydrogen carbonate andsaturated sodium chloride solutions. The solution was dried overmagnesium sulphate and concentrated to afford the crude product (1.5 g).Purification by silica gel chromatography (15-25% ethyl acetate/hexane)afforded the title compound (925 mg, 69%); ν_(max) (CH₂ Cl₂) 3635, 1756,1735 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.86 (3H, d, J 7.1 Hz), 0.97 (3H, d, J 7.0Hz), 1.06 (3H, s), 1.15 (1H, m), 1.32-1.50 (4H, m), 1.39 (3H, s),1.63-2.02 (5H, m), 2.10 (1H, s), 2.22 (2H, m), 2.37 (1H, quintet, J 7.0Hz), 4.31 (1H, t, J 6.4 Hz), 4.91 (1H, d, J 6.9 Hz), 5.32 (1H, dd, J11.2, 0.7 Hz), 5.48 (1H, dd, J 17.7, 0.8 Hz), 6.00 (1H, s), 6.12 (1H,dd, J 18.0, 11.2 Hz); MS (CI) m/z 448/450/452 (MNH₄ ⁺).

Step 2. Mutilin 14-chloroformate-11-dichloroacetate

The product of step 1 (882 mg, 2.04 mmol) was disolved in dry THF (15ml) under argon, cooled in an ice-bath, and treated with trichloromethylchloroformate (0.25 ml, 2.07 mmol) and pyridine (0.21 ml, 2.6 mmol). Theresultant heterogeneous mixture was rapidly stirred for 1 hour, dilutedwith ethyl acetate and washed with saturated sodium chloride solution.The solution was dried over magnesium sulphate and concentrated toafford the title compound which was used without purification (982 mg,97%); ν_(max) (CH₂ Cl₂) 1760, 1737 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.83 (3H, d, J7.1 Hz), 0.88 (3H, d, J 7.1 Hz), 1.13 (3H, s), 1.16 (1H, m), 1.37-1.54(3H, m), 1.48 (3H, s), 1.61-1.92 (4H, m), 2.13-2.37 (4H, m), 2.46 (1H,quintet, J 7.0 Hz), 4.93 (1H, t, J 6.8 Hz), 5.31 (1H, d, J 17.2 Hz),5.37 (1H, d, J 10.7 Hz), 5.61 (1H, t, J 8.4 Hz), 5.99 (1H, s), 6.25 (1H,dd, J 17.5, 11.2 Hz); MS (EI) m/z 498-492 (M⁺).

Step 3. Mutilin 11-dichloroacetate-14-(N-p-methoxysulphonylcarbamate)

The product of Step 2 (250 mg, 0.51 mmol) was disolved indichloromethane (5 ml) under argon and treated withp-methoxysulphonamide (187 mg, 1.0 mmol) in dimethylaminopyridine (5mg). After stirring at room temperature for 3 hours the solution wasdiluted with dichloromethane and washed with 1M hydrochloric acid. Thesolution was dried over magnesium sulphate and concentrated to affordthe crude product (746 mg). Purification by silica gel chromatography(50% ethyl acetate/hexane) afforded the title compound (294 mg, 90%);ν_(max) (CH₂ Cl₂) 3368, 1736 cm⁻¹ ;¹ H NMR (CDCl₃) 0.53(3H, d, J 6.7Hz), 0.83 (3H, d, J 7.0 Hz), 0.99 (3H, s), 1.06-1.89 (8H, s), 1.35 (3H,s), 1.94-2.29 (4H, m), 2.45 (1H, m), 3.88 (3H, s), 4.86 (1H, d, J 6.8Hz), 5.09 (1H, d, J 17.6 Hz), 5.19 (1H, d, J 11.2 Hz), 5.52 (1H, d, J8.0 Hz), 5.96 (1H, s), 6.16 (1H, dd, J 17.6, 11.2 Hz), 6.99 (2H, d, J8.9 Hz), 7.94 (2H, d, J 8.9 Hz); MS (CI) m/z 665/663/661(MNH₄ ⁺).

Step 4. Mutilin 14-(N-p-methoxysulphonylcarbamate)

The product of Step 3 (262 mg, 0.41 mmol) was disolved in THF (3 ml) andmethanol (1 ml) and treated with 1M sodium hydroxide (1 ml, 1.0 mmol).After 1 hour the solution was diluted with ethyl acetate and washed with1M hydrochloric acid and water. The solution was dried over magnesiumsulphate and concentrated to afford the crude product (260 mg).Purification by silica gel chromatography (50% ethyl acetate/hexane)afforded the title compound (206 mg, 95%); ν_(max) (CH₂ Cl₂) 3367, 1736cm⁻¹ ; ¹ H NMR (CDCl₃) 0.53 (3H, d, J 6.7 Hz), 0.83 (3H, d, J7.0 Hz),1.08 (1H, m), 1.10 (3H, s), 1.25-1.75 (8H, m), 1.35 (3H, s), 1.97 (2H,m), 2.20 (3H, m), 3.29 (1H, dd J 10.2, 6.6 Hz), 3.88 (3H, s), 5.09 (1H,dd, J 17.4, 1.3 Hz), 5.24 (1H, d, J 11.0, 1.2 Hz), 5.61 (1H, d, J 8.4Hz), 6.28 (1H, dd, J 17.4, 11.0 Hz), 6.98 (2H, d, J 9.0 Hz), 7.43 (1H,s), 7.93 (2H, d, J 9.0 Hz); MS (CI) m/z 551(MNH₄ ⁺); (Found: C, 63.13;H, 7.54; N, 2.61. C₂₈ H₃₉ NO₇ S requires C, 63.02; H, 7.37; N, 2.62).

EXAMPLE 58 Mutilin 14-[N-(4-hydroxybenzoyl)carbamate]

Step 1. 11-O-Dichloroacetylmutilin

Mutilin (4.0 g, 12.5 mmol) was dissolved in dry tetrahydrofuran (20 ml)and treated with pyridine (1.31 ml, 16.2 mmol), dichloroacetic anhydride(3.29 g, 13.7 mmol), and N,N-dimethylaminopyridine (20 mg). The reactionwas stirred under argon for 2 h at room temperature. Reaction mixturepartitioned between ethyl acetate and water. The organic phase waswashed with 1.0M HCl, water and saturated sodium chloride solutionbefore drying (MgSO₄). Purification was accomplished by chromatographyon silica gel. The product was isolated as a crystalline solid (3.57 g,66%); ν_(max) (CH₂ Cl₂) 3635, 2936, 1756, 1735 and 1463; ¹ H NMR (CDCl₃)0.86 (3H, d, J 7.1 Hz), 0.97 (3H, d, J 7.0 Hz), 1.06 (3H, s) (1H, m)1.39 (3H, s), 1.32-1.50 (4H, m), 1.63-2.02 (5H, m), 2.10 (1H, s), (2H,m), 2.37 (1H, quint., J 6.5 Hz), 4.31 (1H, t, J 6.4 Hz), 4.91 (1H, d, J6.9 Hz), 5.32 (1H, dd, J 11.2, 0.7 Hz), 5.48 (1H, dd, J 17.7, 0.7 Hz),6.00 (1H, s), 6.12 (1H, dd, J 18.0, 11.2 Hz); MS (NH3DCI) m/z448,450,452 (MNH₄ ⁺).

Step 2. 11-O-Dichloroacetylmutilin-14-[N-(4-acetoxybenzoyl)carbamate]

A solution of 4-acetoxybenzoylisocyanate (6 mmol) in dichloroethane (20ml) (prepared as described in Example 33, Step 1) was treated with11-O-dichloroacetylmutilin (650 mg, 1.5 mmol) and the title compoundisolated as described in Example 31, Step 2 (716 mg, 72%): ν_(max) (CH₂Cl₂) 3420, 2943, 1779, 1734, 1604 and 1479; ¹ H NMR (CDCl₃) 0.80 (3H, d,J 6.5 Hz), 0.87 (3H, d, J 7.0 Hz), 1.11-1.23 (4H, m), 1.38-1.93 (11H,m), 2.14-2.32 (5H, m), 2.56-2.62 (1H, m), 4.96 (1H, d, J 6.7 Hz), 5.33(1H, d, J 17.6 Hz), 5.36 (1H, dd, J 11.1 Hz), 5.75 (1H, d, J 8.1 Hz),5.99 (1H, s), 6.44 (1H, dd, J 17.3, 11.3 Hz), 7.22 (2H, d, J 8.7 Hz), ),7.84 (2H, d, J 8.7 Hz), 7.89 (1H, bs): MS (ESI, +ve ion) m/z 653 (MNH₄⁺); (Found: C, 60.34; H, 6.42; N, 2.13. C₃₂ H₃₉ Cl₂ NO₈ requires C,60.38; H, 6.18; N, 2.20)

Step 3. Mutilin 14-[N-(4-hydroxybenzoyl)carbamate]

11-O-Dichloroacetylmutilin-14-[N-(4-acetoxybenzoyl)carbamate](671 mg,1.05 mmol) was dissolved in tetrahydrofuran (5 ml) and methanol (1.0 ml)before treating with 1.0M sodium hydroxide (3.2 ml, 3.2 mmol). Thereaction was stirred at room temperature for 1 h. The reaction waspartitioned between ethyl acetate and 1.0M HCl and the organic phasewashed with water, sodium hydrogen carbonate solution, and finallybrine. After drying (MgSO₄) the crude product was purified bychromatography on silica gel, loading and eluting with 50% ethyl acetatein hexane followed by ethyl acetate. The title compound was isolated asa solid (409 mg, 80%).

EXAMPLE 59 Mutilin 14-[N-(4-hydroxymethylbenzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxymethylbenzoyl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-formylbenzoyl)carbamate] (250 mg, 0.49 mmol) (prepared asdescribed in Example 42, Step 1) was dissolved in dry tetrahydrofuran(2.5 ml) and treated with diisobutyl aluminium hydride (0.54 ml of 1.0Msolution in toluene, 0,8 mmol). After stirring at room temperature for15 minutes the reaction was partitioned between ethyl acetate and water.After washing the organic phase with water, saturated sodium hydrogencarbonate solution and brine the solution was dried (MgSO₄).Purification was accomplished by chromatography on silica gel elutingwith mixtures of ethyl acetate in hexane. The title compound wasisolated as a foam (184 mg, 73%); ν_(max) (CH₂ Cl₂) 3605, 3426, 2930,1776, 1731, 1698, 1613, and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) 1.00 (3H, d, J6.4 Hz), 1.31 (3H, d, J 6.8 Hz), 1.07-1.60 (12H, m), 1.69-1.73 (2H, m),1.91-2.04 (2H, m), 2.15-2.24 (1H, m), 2.53 (1H, dd, J 15.2, 10.1 Hz),2.90 (1H, q, J 6.3 Hz), 3.22 (3H, s), 3.42-3.50 (1H, m), 4,79 and 4.81(2H, s+s), 5.00 (1H, d, J 17.4 Hz), 5.30 (1H, d, J 10.7 Hz), 5.85 (1H,d, J 9.9 Hz), 6.72 (1H, dd, J 17.4, 10.7 Hz), 7.49 (2H, d, J 8.2 Hz),7.82 (1H, d, J 8.3 Hz), 8.00 (1H, bs); MS (NH₃ DCI) m/z 512 (MH⁺), m/z529 (MNH₄ ⁺).

Step 2. Mutilin 14-[N-(4-hydroxymethylbenzoyl)carbamate]

The product of Step 1 (164 mg, 0.32 mmol) in dioxane (2.0 ml) wastreated with a saturated solution of zinc chloride in conc. HCl (0.5ml), as for Example 1 Step 2, to afford the title compound (52 mg, 33%);ν_(max) (CH₂ Cl₂) 3604, 3431, 1778, 1733, 1714, and 1613 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.81 (3H, d, J 6.6 Hz), 0.88 (3H, d, J 7.0 Hz), 1.19-1.81 (16H,m), 1.86 (1H, bs), 2.10-2.37 (4H, m), 3.37 (1H, dd, J 10.5, 6.5 Hz),4.79 (2H, bs), 5.23 (1H, dd, J 17.4, 1.4 Hz), 5.38 (1H, dd, J 11.0, 1.4Hz), 5.83 (1H, d, J 8.5 Hz), 6.55 (1H, dd, J 17.3, 11.0 Hz), 7.50 (1H,d, J 8.2 Hz), 7.80 (1H, d, J 8.3 Hz), 7.96 (1H, bs); MS (NH₃ DCl) m/z498 (MH⁺), m/z 515 (MNH₄ ⁺).

EXAMPLE 60 Mutilin 14-[N-(4-methanesulfonamidobenzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy 11-oxo-4-epi-mutilin14-[N-(4-aminobenzoyl)carbamate]

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-nitrobenzoyl)carbamate] (460 mg, 0.87 mmol) was converted tothe title compound by the method described in Example 34 (268 mg, 64%):ν_(max) (CH₂ Cl₂) 3405, 2930, 1771, 1698, 1623, and 1477 cm⁻¹ ; ¹ HNMR(CDCl₃) 0.89 (3H, d, J 6.9 Hz), 1.00 (3H, d, J 6.4 Hz), 1.07-1.61(12H, m) 1.69-1.76 (2H, m), 1.94-2.04 (2H, m) 2.15-2.24 (1H, m), 2.52(1H, dd, J 15.2, 10.1 Hz), 2.91 (1H, q, J 6.4 Hz), 3.22 (3H, s),3.42-3.50 (1H, m), 4.15 (2H, bs), 5.00 (1H, d, J 17.5 Hz), 5.29 (1H, d,J 10.7 Hz), 5.83 (1H, d, J 9.9 Hz), 6.64-6.80 (3H, m), 7.66 (2H, d, J8.6 Hz), 7.86 (1H, bs); MS (NH₃ DCI) m/z 497 (MH⁺).

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-methanesulfonamidobenzoyl)carbamate]

(3R)-3-Deoxo-11-3-methoxy-11-oxo-4-epi mutilin14-[N-(4-aminobenzoyl)carbamate] (248 mg, 0.50 mmol) was dissolved indry dichloromethane (5 ml) whilst under argon at room temperature. Thereaction was treated with pyridine (0.132 ml, 1.65 mmol) andmethanesulfonyl chloride (0.126 ml, 1.65 mmol) which were added in threeseparate portions over a period of 3 h. The reaction was diluted withdichloromethane and washed with saturated sodium hydrogen carbonate,1.0M HCl, water, and saturated sodium chloride solution before drying(MgSO₄). The crude material was triturated with hexane to give the titlecompound as a solid (236 mg, 82%); ν_(max) (KBr disc) 1762, 1695, 1603cm⁻¹ ; ¹ H NMR (d₆ -acetone) 0.94 (3H, d, J 6.9 Hz), 1.01 (3H, d, J 6.4Hz), 1.0-1.97 (12H, m), 2.04-2.10 (m, obscured by solvent), 2.53 (1H,dd, J 15.6, 10.5 Hz), 2.80-3.00 (m, obscured by solvent), 3.11 (3H, s),3.21 (3H, s), 3.46-3.52 (1H, m), 4.99 (1H, d, J 17.5 Hz), 5.30 (1H, d, J9.9 Hz), 6.82 (1H, dd, J 17.5, 10.7 Hz), 7.43 (2H, d, J 8.8 Hz), 7.94(2H, d, J 8.7 Hz), 9.11 (1H, bs), 9.91 (1H, s).

Step 3: Mutilin 14-[N-(4-methanesulfonamidobenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-methanesulfonamidobenzoyl)carbamate] (208 mg, 0.36 mmol) wasdissolved in dioxan (2.0 ml) and treated with a saturated solution ofzinc chloride in conc. HCl (0.5 ml), as for Example 1 Step 2, to affordthe title compound (72 mg, 36%); ν_(max) (KBr disc) 1733 and 1608 cm⁻¹ ;¹ H NMR (d₆ -acetone) 0.67 (3H, d, J 6.3 Hz), 0.82 (3H, d, J 7.1 Hz),0.91-1.71 (15H, m), 1.96-2.05 (1H, m), 2.19 (1H, quint., J 6.8 Hz), 2.26(1H, bs), 2.96 (3H, s), 3.30 (1H, d, J 7.3 Hz, ex. in D₂ O, 3.50 (1H, m,collapse to d in D₂ O, J 5.9 Hz), 5.05 (1H, dd, J 11.0, 1.7 Hz), 5.11(1H, dd, J 17.7, 1.7 Hz), 5.64 (1H, d, J 8.3 Hz), 6.32 (1H, dd, J 17.7,11.1 Hz), 7.26 (1H, d, J 8.8 Hz), 7.80 (1H, d, J 8.7 Hz), 9.72 (1H, bs,ex, in D₂ O); MS (NH₃ DCI m/z 561 (MNH₄ ⁺).

EXAMPLE 61 Mutilin 14-[N-(4-Aminosulphonylphenyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-aminosulphonylphenyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (336 mg, 1 mmol) indry CH₂ Cl₂ (7.5 ml) was treated with 4-chlorosulphonylphenyl isocyanate(283 mg, 1.3 mmol) and N,N-di-iso-propylethylamine (1 drop) and thesolution was kept at room temperature, with exclusion of moisture, for 2days, and then in a refrigerator for 70 h. The solvent was then removedusing a rotary eveporator and replaced by tetrahydrofuran (7.5 ml).0.880 S.G. Aqueous ammonia (0.5 ml) was then added and the mixture wasstirred for 1.5 h. The solution was diluted with ethyl acetate (50 ml)and was washed with brine. The aqueous layer was re-extracted with ethylacetate (50 ml) and the combined ethyl acetate solutions were washedwith 1M HCl (5 ml)/brine (15 ml). The solution was dried (MgSO₄) and thesolvent was removed by evaporation under reduced pressure to yield acolourless foam. The foam was chromatographed on silica gel, using 4:6,followed by 1:1, followed by 7:3 ethyl acetate--hexane, to give(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4epi-mutilin14-[N-(4-aminosulphonylphenyl)]-carbamate as a colourless solid foam(460 mg, 86%); ν_(max) (CH₂ Cl₂) 3420, 3335, 2980, 2930, 1731, 1698,1592, 1218, and 1163 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.87 (3H, d, J 6.9 Hz), 1.00(3H, d, J 6.37 Hz), 1.01-1.8 (ca 14H, m), 1.9-21. (2H, m), 2.1-2.3 (1H,m), 2.50 (1H, dd, J 10.0, 15.2 Hz), 2.94 (1H, q, J 6.4 Hz), 3.23 (3H,s), 3.4-3.6 (1H, m), 4.84 (2H, s), 5.03 (1H, d, J 17.5 Hz), 5.34 (1H, d10.7 Hz), 5.81 (1H, d, J 9.8 Hz), 6.70 (1H, dd, J 10.6, 17.5 Hz), 6.88(1H, s), 7.59 (2H, d, J 8.7 Hz), 7.88 (2H, d, J 8.8 Hz); MS (CI) m/z 550(MNH₄)⁺.

Step 2. Mutilin 14-[N-(4-Aminosulphonylphenyl)]-carbamate

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin[N-(4-aminosulphonyl-phenyl)]-carbamate (410 mg, 0.77 mmol) in dioxane(7.5 ml) was treated with a saturated solution of zinc chloride in conc.HCl (1 ml) and the solution was stirred at room temperature for 5 hours.As the reaction had not proceded to completion more of a saturatedsolution of zinc chloride in conc. HCl (2 ml) was added and stirring wascontinued for 2 h. The mixture was diluted with ethyl acetate (50 ml)and the solution was washed with saturated NaCl solution (20 ml) andsaturated NaHCO₃ solution (20 ml). The solution was dried (MgSO₄) andthe solvent was removed by evaporation under reduced pressure to yield acolourless solid. The solid was chromatographed on silica gel, loadingin CH₂ Cl₂ /toluene containing a trace of ethyl acetate and using 1:1ethyl acetate--hexane, followed by ethyl acetate--toluene mixtures; 3:7;followed by 6:4; followed by 1:1; to give mutilin[N-(4-aminosulphonylphenyl)]-carbamate as a colourless solid (281 mg,70%); ν_(max) (KBr) 1725, 1595, 1530, 1337, 1317, 1228 and 1160 cm⁻¹ ; ¹H NMR [(CD₃)₂ SO] 0.90 (3H, d, J 6.8 Hz), 1.00 (3H, d, J 6.3 Hz),1.0-1.8 (14H, m, including singlets at 1.08 and 1.43), 2.04-2.27 (4H,m), 2.42 (1 h, br s), 3.45 (1H, br t, J ca. 5.8 Hz; d, J 5.5 Hz after D₂O exch.), 4.52 (1H, d, J 6.1 Hz, exch D₂ O), 5.05-5.15 (2H, m), 5.38(1H, br d, J 7.8 Hz), 6.27 (1H, dd, J 11.1, 17.7 Hz), 7.21 (2H, s, exchD₂ O), 7.59 (2H, d, J 8.8 Hz), 7.71 (2H, d, J 8.8 Hz), 9.82 (1H, s);MS(CI) m/z 536 (M+NH₄ ⁺).

EXAMPLE 62 Mutilin14-{N-[4-([2R]-2,3-dihydroxypropyloxy)-benzoyl]}-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxybenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-acetoxybenzoyl)]-carbamate (Example 37, Step 2) (809 mg, 1.5mmol) in 1,4-dioxan (10 ml) was treated with aqueous 1M NaOH (4.5 ml)and the mixture was stirred for 2.5 h. Ethyl acetate (100 ml) andaqueous 1M HCl (10 ml), followed by water (50 ml) were added. Afterseparation of the layers the aqueous layer was washed with ethylacetate. The combined ethyl acetate layers were dried (MgSO₄) andevaporated. The residue was chromatographed on silica gel, loading withCH₂ Cl₂, and eluting with ethyl acetate/hexane mixtures: 1:1, followedby 6:4, followed by 7:3, followed by 8:2, to give the title compound(677 mg, 90%) as a colourless solid; ν_(max) (CH₂ Cl₂) 3565, 3417, 2930,1774, 1729, 1698, 1608, 1478, 1187, and 1167 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90(3H, d, J 6.8 Hz), 1.00 (3H, d, J 6.3 Hz), 1.0-1.8 (14 H, m, including sat 1.20 and s at 1.31), 1.99 (2H, m), 2.21 (1H, dt, J 10.0, 2.7 Hz),2.52 (1 h, dd, J 10.1, 15.2 Hz), 2.91 (1H, q, J 6.4 Hz), 3.23 (3H, s),3.46 (1H, m), 5.01 (1H, d, J 17.5 Hz), 5.28 (1H, d, J 10.8 Hz), 5.84(1H, d, J 9.9 Hz), 6.71 (1H, dd, J 10.7, 17.5 Hz), 6.94 (2H, d, J 8.7Hz), 7.75 (2H, d, J 8.7 Hz), 7.96 (1H, s); MS(CI) m/Z 498 (MH⁺), 515(MNH₄ ⁺).

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[4-([2R]-2,3-dihydroxypropyloxy)-benzoyl]}-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxybenzoyl)]-carbamate (497 mg, 1 mmol) in tert-butanol (5ml) under an atmosphere of argon was warmed to effect dissolution, andthen treated with sodium hydride (40 mg of a 60% dispersion in oil, 1mmol). When effervescence had ceased (ca. 30 min) (R)-(+)-glycidol (0.06ml, 74 mg, 1 mmol) in dichloromethane (2.5 ml) was added, followed bytitanium(IV) isopropoxide (0.36 ml, 341 mg, 1.2 mmol). The mixture wasstirred under an argon atmosphere for 18 h, and then heated under reflux(oil bath 50°) for 6.5 h. Ethyl acetate (50 ml)/1M HCl (25 ml) wereadded the layers separated. The aqueous layers was re-extracted withethyl acetate and combined ethyl acetate layers were washed with brineand dried (MgSO₄). After removal of solvent the crude product waschromatographed on silica gel, loading in CH₂ Cl₂, and eluting withethylacetate/hexane mixtures: 1:1, followed by 6:4, followed by 7:3,followed by 8:4. Fractions containing the product were combined andevaporated to give the title compound as a solid foam (297 mg, 52%);ν_(max) (CH₂ Cl₂) 3585, 2931, 1774, 1729, 1698, 1605, 1478, and 1171cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90(3H, d, J 6.8 Hz), 1.00 (3H, d, J 6.3 Hz),1.0-1.6 (12H, m, including s at 1.20 and s at 1.30) 1.70 (1H, d, J 9.9Hz), 1.70 (1H, d, J 5.7 Hz), 1.9-2.3 (4H, m; 1H exch. D₂ O), 2.53 (1H,dd, J 10.1, 15.2 Hz), 2.60 (1H, br s, exch. D₂ O), 2.90 (1H, q, J 6.4Hz), 3.22 (3H, s), 3.41-3.50 (1H, m), 3,7-4.0 (2H, m, signal sharpens onD₂ O exch.), 4.07-4.16 (3H, m), 5.01 (1H, d, J 17.4 Hz), 5.29 (1H, d, J17.4 Hz), 5.29 (1H, J 8.8 Hz), 5.84 (1H, d, J 10.6, 17.4 Hz), 6.97 (2H,d, J 8.8 Hz), 7.79 (2H, d, J 8.8 Hz), 8.00 (1H, s); MS (Electrospray)m/z 572 (MH⁺), 1143 (2M+H)⁺.

Step 3. Mutilin14-{N-[4-([2R]-2,3-dihydroxypropyloxy]-benzoyl]}-carbamate

The product of Step 2 (256 mg, 0.45 mmol) in dioxane (3ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1.0 ml), as forExample 1 Step 2, to afford the title compound (105 mg, 42%); ν_(max)(KBr) 1761, 1732, 1605, 1497, 1255, 1204, and 1174 cm⁻¹ ; ¹ H NMR (CDCl₃+CD₃ OH) 0.77 (3H, d, J 6.4 Hz) 0.85 (3H, d, J 6.9 Hz), 1.0-2.4 (19H, m,including s at 1.15 and s at 1.48), 3.33 (1 h, d, J 6.5 Hz), 3.60-3.8392 h, m), 3.9-4.2 (3H, m), 5.19 (1H, dd, J 1.4, 17.4 Hz), 5.33 (1H, dd,J 1.3, 11.0 Hz), 5.78 (1H, d, J 8.3 Hz), 6.51 (1 h, dd, J 11.0, 17.3Hz), 6.92 (2H, d, J 8.8 Hz), 7.74 (2H, d, J 8.8 Hz); MS (Electrospray)m/z 558 (MH⁺), 1115 (2M+H⁺).

EXAMPLE 63 Mutilin 14-(N-Chloroacetyl)-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-chloracetyl)-carbamate

(3R)-3-Deoxo1 1-deoxy-3-methoxy-1-oxo-4-epi-mutilin (335mg, 1.0 mmol)and silver cyanate (225 mg, 1.5 mmol) in dichloromethane (5 ml) under anargon atmosphere in a flask wrapped in aluminium foil was treated withchloroacetyl chloride (0.12 ml, 169 mg, 1.5 mmol), and the mixture wasstirred for 1 h. The mixture was filtered through kieselguhr andevaporated. Toluene was then added and removed. The residue waschromatographed on silica gel, loading in dichloromethane and elutingwith ethyl acetate/hexane mixtures: 2:8, followed by 3:7 to give thetitle compound (456 mg, quant.); ν_(max) (CH₂ Cl₂) 3381, 2981, 1787,1754, 1728, 1698, 1489, 1459, and 1198 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.83 (3H,d, J 6.8 Hz), 1.00 (3H, d, J 6.4 Hz), 1.01-1.40 (10 H, m, including s at1.20 and s at 1.23), 1.40-1.56 (2H, m), 1.62 (1H, d, J 15.3 Hz), 1.73(1H, d, J 11.3 Hz), 1.8-2.1 (2H, m), 2.20 (1H, dt, J 2.8, 12.7 Hz), 2.51(1H, dd, J 10.1, 15.3 Hz), 2.86 (1H, q, J 6.3 Hz), 3.22 (3H, s),3.35-3.50 (1H, m), 4.51 (2H, s), 5.03 (1H, d, J 17.5 Hz), 5.32 (1H, d, J10.7 Hz), 5.75 (1H, d, J 10.0 Hz) 6.60 (1H, dd, J 10.7, 17.5 Hz), 7.88(1H, s, exch D₂ O); MS(CI) m/z 471 (MNH₄ ⁺).

Step 2. Mutilin 14-(N-Chloroacetyl)-carbamate

The product of Step 2 (400 mg, 0.88 mmol) in dioxane (4.5 ml) wastreated with a saturated solution of zinc chloride in conc. HCl (1.5ml), as for Example 1 Step 2, to afford the title compound (185 mg,52%); ν_(max) (CH₂ Cl₂) 3564, 3388, 2960, 2895, 1783, 1755, 1732, 1605,and 1478 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.74 (3H, d, J 6.8 Hz), 0.89 (3H, d, J7.1 Hz), 1.0-1.3 (4H, m, including s at 1.19), 1.3-1.9 (12H, m,including s at 1.44), 2.0-2.4 (4H, m), 3.37 (1H, dd, J 6.6, 10.7 Hz; d,6.5 Hz after D₂ O exch.), 4.47 (2H, s), 5.23 (1H, dd, J 1.4, 17.4 Hz),5.38 (1H, dd, J 1.3, 10.9 Hz), 5.72 (1H, d, J 8.5 Hz), 6.47 (1H, dd, J11.0, 17.4 Hz), 7.81 (1H, exch D₂ O); MS(CI) m/z 457 (MNH₄ ⁺).

EXAMPLE 64 19,20-Dihydromutilin 14-[N-(4-hydroxybenzoyl)]-carbamate

Mutilin 14-[N-(4-hydroxybenzoyl)]-carbamate (130 mg) in ethyl acetate(10 ml) containing 10% Pd-C catalyst (44 mg) and the mixture washydrogenated at atmospheric pressure for 30 min. The mixture wasfiltered through kieselguhr and the ethyl acetate was removed.chloroform/methanol was then added and removed and the chloroform wasadded and removed to leave the title compound (131 mg) as a solid foam;ν_(max) (KBr) 1781, 1725, 1697, 1609, 1459, 1299, and 1201 cm⁻¹ ; ¹ HNMR (CDCl₃ +CD₃ OD+D₂ O) 0.7-1.27 (15H, m), 1.27-1.90 (10 H, m,including s at 1.46), 1.9-2.5 (5H, m), 3.39 (1 h, d, J 5.4 Hz), 5.65(1H, d, J 7.9 Hz), 6.84 (2H, d, J 8.7 Hz), 7.69 2H, d, J 8.7 Hz); MS(CI)m/z 486 (MH⁺) 503 (MNH₄ ⁺); MS(Electrospray) 503 (MNH₄ ⁺) 544 (MNH₄ ⁺+MeCN).

EXAMPLE 65 Mutilin 14-[N-(3-Amino-1,2,4-triazolylthioacetyl)]-carbamate

Mutilin 14-(N-Chloroacetyl)-carbamate (100 mg, 0.23 mmol) inN,N-dimethylformamide (2.5 ml) was treated with3-amino-5-mercapto-1,2,4-triazole (29 mg, 0.25 mmol), followed byN,N-diisopropylethylamine (0.043 ml, 32 mg, 0.25 mmol). The mixture wasstirred for 4.5 h and then ethyl acetate (25 ml) and water (15 ml) wereadded and the mixture was separated. The aqueous phase was re-extractedwith ethyl acetate, and combined ethyl acetate layers were washed withbrine, dried (MgSO₄) and evaporated. the residual oil was taken up indichloromethane and loaded onto a silica gel column. Elution with ethylacetate/hexane (1:1), followed by ethyl acetate, followed by ethylacetate/ethanol gave the title compound, contaminated by a little DMF.The material was taken up in ethyl acetate and washed with water,followed by brine, dried (MgSO₄) and evaporated. Trituration of theresidue with diethyl ether gave the title compound (102 mg, 85%); ¹ HNMR (CDCl₃ +CD₃ OD+D₂ O) inter alia 0.63 (3H, d, J 6.4 Hz), 0.81 (3H, d,J 6.9 Hz), 0.9-1.8 (14H, m, including s at 1.04 and s at 1.32), 1.9-2.3(5H, m), 3.65 and 3.72 (2H, ABq, J 15.2 Hz), 5.08 (1H, dd, J 1.4, 17.3Hz), 5.22 (1H,dd, J 1.3, 11.1 Hz), 5.55 (1H, d, J 8.4 Hz), 6.35 (1H, dd,J 11.0, 17.4 Hz); MS(CI) 520 (MH⁺).

EXAMPLE 66 Mutilin 14-[N-(2-N,N-Diethylaminoethylthioacetyl)]-carbamate

Mutilin 14-(N-Chloroacetyl)-carbamate (100 mg, 0.23 mmol) intetrahydrofuran (2 ml) was treated with N,N-diethylaminoethane thiolhydrochloride (39 mg, 0.23 mmol) followed by 1M aqueous NaOH (0.5 ml).After stirring for 4.5 h ethyl acetate (25 ml) and water (20 ml) wereadded and the layers were separated. The aqueous layer was re-extractedwith ethyl acetate and the combined extracts were washed (MgSO₄) andevaporated. the residue was chromatographed on silica gel, eluting withCH₂ Cl₂ /MeOH/0.880 NH₄ OH mixtures; 95:4.5:0.5, followed by 90:9:1 togive the title compound (20 mg); ¹ H NMR (CDCl₃ +CD₃ OD+D₂ O) 0.73 (3H,d, J 6.4 Hz), 0.85 (3H, d, J 6.9 Hz), 1.00 (6H, t, J 7.1 Hz), 1.1-1.25(4H, s superimposed on m), 1.25-1.9 (11H, m, including s at 1.42),2.0-2.4 (6H, m), 2.53 (4H, q, J 7.1 Hz), 2.65 (4H, br. s), 3.33 (1H, d,J 6.3 Hz), 5.19 (1H, d, J 17.2 Hz), 5.33 (1H, d J 11.0 Hz), 5.70 (1H, d,J 8.3 Hz), 6.46 (1H, dd, J 11.0, 17.4 Hz).

EXAMPLE 67 Mutilin 14-[N-(4-nitrobenzenesulphonyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-nitrobenzenesulphonyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(500 mg) in dry dichloromethane (10 ml) was treated with4-nitrobenzenesulphonamide (508 mg), diisopropylethylamine (0.5 ml), and4-dimethylaminopyridine (5 mg), and the solution was stirred for 2 hoursat room temperature. The solution was diluted with ethyl acetate (100ml) and washed with dilute HCl (100 ml), water (100 ml), and saturatedbrine (100 ml). The solution was dried (sodium sulphate) and the solventwas removed by evaporation under reduced pressure to yield the crudeproduct as a colourless gum.

Step 2. Mutilin 14-[N-(4-nitrobenzenesulphonyl)]-carbamate

The crude (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-nitrobenzenesulphonyl)]-carbamate from Step 1. was dissolved in1,4-dioxane (12 ml) and treated with a saturated solution of zincchloride in conc. HCl (4 ml). The solution was kept at room temperaturefor 4 hours, diluted with ethyl acetate (150 ml) and washed three timeswith water (100 ml portions). The solution was dried (sodium sulphate)and the solvent was removed by evaporation under reduced pressure togive a colourless gum. Chromatography on silica gel using ethylacetate--hexane gave the title compound as a white solid (272 mg);ν_(max) (CH₂ Cl₂) 3624, 3353, 1736, and 1608 cm⁻¹ ; δ_(H) (CDCl₃) 8.32(2H, d, J 8.5 Hz), 8.18 (2H, d, J 8.5 Hz), 6.27 (1H, dd, J 17.5 and 11Hz), 5.60 (1H, d, J 8.3 Hz), 5.22 (1H, d, J 11 Hz), 5.09 (1H, d, J 17.5Hz), 3.30 (1H, dd, J 6.5 and 10 Hz), 2.22 (2H, m), 2.00 (2H, m), 1,8-1.0(overlapping multiplets), 1.35 (3H, s), 1.09 (3H, s), 0.85 (3H, d, J 6.9Hz), 0.51 (3H, d, J 6.7 Hz); MS (CI) m/z 566 (M.NH₄ ⁺).

EXAMPLE 68 Mutilin 14-[N-(4-cyanobenzenesulphonyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-cyanobenzenesulphonyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin 14-chloroformate(400 mg ) in dry dichloromethane (20 ml) was treated with4-cyanobenzenesulphonamide (273 mg), diisopropylethylamine (0.4 ml), and4-dimethylaminopyridine (4 mg), and the solution was stirred for 16hours at room temperature. The solution was diluted with ethyl acetate(100 ml) and washed with dilute HCl (100 ml), water (100 ml), andsaturated brine (100 ml). The solution was dried (sodium sulphate) andthe solvent was removed by evaporation under reduced pressure to yieldthe crude product as a colourless gum.

Step 2. Mutilin 14-[N-(4-cyanobenzenesulphonyl)]-carbamate

The crude (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-cyanobenzenesulphonyl)]-carbamate from Step 1 was dissolved in1,4-dioxane (12 ml) and treated with a saturated solution of zincchloride in conc. HCl (4 ml).

The solution was kept at room temperature for 4 hours, diluted withethyl acetate (150 ml) and washed three times with water (100 mlportions). The solution was dried (sodium sulphate) and the solvent wasremoved by evaporation under reduced pressure to give a colourless gum.Chromatography on silica gel using ethyl acetate--hexane gave the titlecompound as a white foam (185 mg); ν_(max) (CH₂ Cl₂) 3627, 3348, and1735 cm⁻¹ ; δ_(H) (CDCl₃) 8.12 (2H, d, J 8.5 Hz), 7.82 (2H, d, J 8.5Hz), 6.27 (1H, dd, J 17.5 and 11 Hz), 5.60 (1H, d, J 8.4 Hz), 5.21 (1H,d, J 10.5 Hz), 5.10 (1H, d, J 17.5 Hz), 3.30 (1H, dd, J 6.5 and 10 Hz),2.21 (2H, m), 2.00 (2H, m), 1.8-1.0 (overlapping multiplets), 1.33 (3H,s), 1.10 (3H, s), 0.86 (311, d, J 6.9 Hz), 0.51 (3H, d, J 6.9 Hz); MS(CI) m/z 546 (M.NH₄ ⁺).

EXAMPLE 69 Mutilin 14-[N-(4-aminobenzenesulphonyl)]-carbamate

Mutilin 14-[N-(4-nitrobenzenesulphonyl)]-carbamate (265 mg) wasdissolved in ethanol (30 ml) and ethyl acetate (5 ml) and heated togentle reflux with tin(II) chloride (458 mg) for 5 hours under anatmosphere of argon. After cooling, the solvent was evaporated and theresidue was chromatographed over silica gel, eluting with ethylacetate--hexane mixtures. The title compound was obtained as a whitesolid (80 mg); ν_(max) (CH₂ Cl₂) 3407, 1735, 1624 and 1596 cm⁻¹ ; δ_(H)(d₆ -DMSO) 11.23 (1H, s exchange with D₂ O), 7.44 (2H, d, J 8.8 Hz),6.90 (1H, s exchanges with D₂ O), 6.59 (2H, d, J 8.8 Hz), 6.10 (1H, s,exchanges with D₂ O), 6.10 (1H, dd, J 17.7 and 11.2 Hz), 5.32 (1H, d, J7.6 Hz), 4.87 (1H, dd, J 11.2 and 1.4 Hz), 4.78 (1H, dd, J 17.8 and 1.4Hz), 4.51 (1H, d, J 6.0 Hz, exchanges with D₂ O), 3.30 (1H, d), 2.3-1.0(overlapping multiplets), 1.30 (3H, s),0.98 (3H, s), 0.78 (3H, d, J 6.9Hz), 0.48 (3H, d, J 6.3 Hz); MS (CI) m/z 536 (M.NH₄ ⁺).

EXAMPLE 70 Mutilin 14-[N-(6-Ethoxybenzothiazolyl-2-sulphonyl)]-carbamate

Step 1. 11-O-Dichloroacetyl-Mutilin14-[N-(6-Ethoxybenzotriazolyl-2-sulphonyl)]-carbamate

A solution of mutilin 14-chloroformate-11-dichloroacetate (246 mg, 0.5mmol) in dichloromethane (1 ml) was added to an ice-cooled solution of6-ethoxybenzothiazole-2-sulphonamide (130 mg, 0.5 mmol) andN,N-di-isopropylethylamine (0.092 ml, 1.05 eq) in dichloromethane (2ml)-DMF (0.5 ml). The cooling bath was removed and the solution stirredat room temperature for 3 days. The solution was diluted with ethylacetate and washed with dil. HCl with water and with brine. Drying(MgSO₄) and evaporation gave a foam (ca 350 mg) which waschromatographed on silica gel, using 5% methanol-chloroform to give theproduct as a white solid (142 mg): ν_(max) (CHCl₃) 3500, 3368, 1734,1740 (shoulder), 1601 cm⁻¹.

Step 2. Mutilin 14-[N-(6-Ethoxybenzothiazolyl-2-sulphonyl)]-carbamate

The product of step 1 (130 mg, 0.18 mmol) was dissolved in methanol (2ml) and 1N NaOH (0.18 ml) was added. After stirring for 1 hr a furtherportion of 1N NaOH (0.18 ml) was added. After a total of 3 hr themixture was acidified by adding 2N HCl (0.2 ml) and extracted with ethylacetate. The extract was washed with brine, dried (MgSO₄) and evaporatedto give a gum (140 mg). Chromatography on silica gel, using 10%methanol-chloroform gave the title compound as a white solid (96 mg,87%); ν_(max) (CHCl₃) 3370, 1737, 1602 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.59 (3H,d, J 6.7), 0.82 (3H, d, J 6.9), 0.94 (3H, s), 0.9-1.1 (ca 12H, m),1.25-1.7 (ca 15H, m) 1.8-2.25 (ca 4H, m), 3.24 (1H, dd, J 9,7 collapseto d, J 6 with D₂ O), 4.13 (2H, q, J 7), 5.00 (1H, d, J 17), 5.11 (1H,d, J 11), 5.62 (1H, d, J 8), 6.2 (1H, br, collapse to dd, J 17,11 withD₂ O), 7.2 1H, 2.2, 9), 7.35 (1H, d, J 2.3), 8.0 (1H, d, J 9); MS (NH₃DCI) m/z 605 (MH⁺), 622 (MNH₄ ⁺).

EXAMPLE 71 Mutilin 14-[N-(2,4-Dimethylthiazolyl-5-sulphonyl)]-carbamate

Step 1.11-O-Dichloroacetyl-Mutilin-14-[N-(2,4-Dimethylthiazolyl-5-sulphonyl)]-carbamate

A solution of mutilin 14-chloroformate-11-dichloroacetate (493mg, 1mmol) in dichloromethane (4 ml) was added to an ice-cooled solution of2,4-dimethylthiazole-5-sulphonamide (192 mg, 1 mmol) andN,N-di-isopropylethylamine (0.175 ml, 1 mmol) in dichloromethane (5ml)-DMF (0.5 ml). The cooling bath was removed and the solution stirredat room temperature overnight, refluxed for 5 hr and left again at roomtemperature overnight. Examination by tlc showed that reaction wasalmost complete. Evaporation of solvent followed by chromatography onsilica gel, using 2% methanol-chloroform gave an impure product whichwas further chromatographed using 1:1 ethyl acetate-hexane. The productwas obtained as a white solid (188 mg); ν_(max) (CHCl₃) 3378, 1735 cm⁻¹; ¹ H NMR (CDCl₃) inter alia 2.70 (3H, s), 4.89 (1H, d, J 7), 5.17 (1H,d, J 17 ), 5.24 (1H, d, J 11), 5.58 (1H, d, J 8), 5.98 (1H, s) 6.21 (1H,dd, J 17, 11), 7.5-7.8 (1H, br); MS (NH₃ DCI) m/z 649/651 (MH⁺).

Step 2. Mutilin 14-[N-(2,4-Dimethylthiazolyl-5-sulphonyl)]-carbamate

The product of Step 1 (175 mg, 0.27 mmol) was dissolved in methanol (5ml)-tetrahydrofuran (2 ml) and 1N NaOH (0.50 ml; 1.85 eq) was added.After 3 hr at room temperature the mixture was acidified by adding 2NHCl (0.25 ml) and extracted with ethyl acetate (50 ml). The extract waswashed with water and with brine, dried (MgSO₄) and evaporated to give agum (140 mg). Chromatography on silica gel, using 1:1 ethylacetate-hexane gave the title compound as a white foam (85 mg); ν_(max)(CHCl₃) 3694, 3562, 1736 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.61 (3H, d, J 6.8),0.86 (3H, d, J 7), 1.1-1.8 (ca 15H, m), 2.0-2.25 (ca 5H, m) 2.64 (3H,s),2.70 (3H, s), 3.32 (1H, d, J 6.5), 5.14 (1H, dd, J 17, 1.3), 5.30 (1H,dd, j 10, 1.3), 5.66 (1H, d, J 8), 6.32 (1H, dd, J 17,11), 7.71 (1H, br,exch D₂ O); MS (EI) m/z 538 (M⁺). Found: 538.2171, C₂₆ H₃₈ N₂ O₆ S₂requires 538.2172.

EXAMPLE 72 Mutilin 14-[N-(Thiophene-2-sulphonyl)]-carbamate Step 1.11-O-Dichloroacetyl-Mutilin 14-[N-(Thiophene-2-sulphonyl)]-carbamate

A solution of mutilin 14-chloroformate-11-dichloroacetate (370 mg, 0.75mmol) in dichloromethane (1 ml) was added to an ice-cooled solution ofthipohene-2-sulphonamide (122 mg, 0.75 mmol), N,N-di-isopropylethylamine(0.13 ml) and 4-dimethylaminopyridine (2mg) in dichloromethane (3ml)-DMF (0.4 ml). The cooling bath was removed and the solution stirredat room temperature overnight. The solution was diluted with ethylactetate and washed with dil. HCl and with brine. The solution was dried(MgSO₄) and evaporated to give a gum which was chromatographed on silicagel, using 5% acetone-toluene to give the product as a white foam (280mg): ν_(max) (CHCl₃) 3381, 1736 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 4.88(1H, d, J 6.9), 5.15 (1H, d, J 17), 5.24 (1H, d, J 11), 5.58 (1H, dd, J5, 1.4), 7.85 (1H, dd, J 3.8, 1.4); MS (NH₃ DCI) m/z 637/639 (MNH₄ ⁺).Step 2. Mutilin 14-[N-(Thiophene-2-sulphonyl)]-carbamate

The product from Step 1 (248 mg, 0.4 mmol) was dissolved in methanol (4ml) and 1N NaOH (0.8 ml, 2 eq) was added. After 4 hr the mixture wasacidified by adding 2N HCl and extracted with ethyl acetate. The extractwas washed with brine, dried (MgSO₄) and evaporated to give a gum whichwas purified by chromatography on silica gel, using 1:1 ethylacetate-hexane. The title compound was obtained as a white solid (155mg); ν_(max) (CHCl₃) 3380, 1736 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.57 (3H, D, J7), 1.11 (3H, s) 1.38 (3H, s), 1.2-1.75 (ca 11H, m), 1.92-2.05 (2H, mm),2.22 (2H, q, J 8), 3.31 (1H, dd, J 10, 6.8), 5.12 (1H, dd, J 17, 1.4),5.28 (1H, dd, J 11, 1.4), 5.67 (1H, d, 8.4), 7.11 (1H, dd, J 5, 4), 7.69(1H, dd J 5, 1.2), 7.84 (1H, dd, J 4, 1.2), 7.5 (11H, br); MS (NH₃ DCI)m/z 527 (MNH₄ ⁺).

EXAMPLE 73 Mutilin14-[N-(5-Acetamido-1,3,4-thiadiazolyl]-2-sulphonyl)]-carbamate

Step 1. 11-O-Dichloroacetyl-Mutilin14-[N-(5-Acetamido-1,3,4-thiadiazolyl-2-sulphonyl)carbamate]

A solution of mutilin 14-chloroformate-11-dichloroacetate (246 mg, 0.5mmol) in DMF (1 ml) was added to a solution of5-acetamido-1,3,4-thiadiazole-2-sulphonamide (111 mg, 0.5 mmol),N,N-di-isopropylethylamine (0.09 ml, 1.05 eq) and4-dimethylaminopyridine (cat.) in DMF (1 ml). The solution was stirredat room temperature overnight, diluted with ethyl actetate and washedwith dil. HCl and with brine. The solution was dried (MgSO₄) andevaporated to give a gum which was chromatographed on silica gel, using10% methanol-chloroform to give the product as a white solid (97 mg).

Step 2. Mutilin14-[N-(5-Acetamido-1,3,4-thiadiazolyl-2-sulphonyl)]-carbamate

The product of Step 1 (95 mg) was dissolved in THF (0.5 ml) and methanol(1.5 ml). 1N NaOH (0.28 ml, 2 eq) was added and the solution left atroom temperature for ca 24 hr during which time a further portion of 1NNaOH (0.14 ml) was added. The solution was acidified with 2N HCl andextracted with ethyl acetate. The extract was washed with brine, dried(MgSO₄) and evaporated to give a gum which was purified bychromatography on silica gel, using 10% methanol-chloroform andrechromatographed using using ethyl acetate. The title compound wasobtained as a white solid (19 mg, 24%); ¹ H NMR (d₆ -acetone-D₂ O) interalia 2.36 (3H, s), 3.54 (1H, d J 6), 5.0-5.1 (ca 2H, m), 5.58 (1H, d, J8), 6.18 (1H, dd, J 17, 11); MS (Electrospray) m/z 569 (MH⁺).

EXAMPLE 74 Mutilin 14-[N-(3-amino-4-methoxybenzoyl)]-carbamate

Step 1. 4-Methoxy-3-nitrobenzoylisocyanate

Silver cyanate (967 mg, 6.5 mmol) was suspended in dry dichloromethane(6 ml) under an atmosphere of argon. A solution of4-methoxy-3-nitrobenzoyl chloride (1.29 g, 6.0 mmol) in dichloromethane(4 ml) was added and the heterogeneous mixture stirred at reflux undersubdued light. After 40 minutes the reaction was allowed to cool andfiltered through Kieselguhr. The solution was used immediately in thenext reaction. ν_(max) (CH₂ Cl₂) 2337 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-methoxy-3-nitrobenzoyl)]-carbamate

The solution from step 1 was cooled to 0° C. and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg, 1.5 mmol)and the reaction stirred for 1 hour. The mixture was diluted withdichloromethane and washed with 1.0M hydrochloric acid followed by waterand saturated sodium chloride solution. After drying (MgSO₄) the crudematerial was purified by chromatography on silica gel eluting with 40%ethyl acetate in hexane to yield the title compound (770 mg, 92%); m.p.178-180° C.; ν_(max) (CH₂ Cl₂) 3300, 2980, 1777, 1697, 1619 and 1476cm⁻¹; ¹ H NMR (CDCl₃) 0.90 (3H, d, J 6.8 Hz), 0.99 (3H, d, J 6.4 Hz),1.07-1.58 (12H, m) including 1.21 (3H, s) and 1.31 (3H, s), 1.68-1.76(2H, m), 1.94-2.04 (2H, m), 2.20 (1H, m), 2.54 (1H, dd, J 15.3, 10.0Hz), 2.90 (1H, q, J 6.2 Hz), 3.24 (3H, s), 3.48 (1H, m), 4.05 (3H, s),5.01 (1H, d, J 17.4 Hz), 5.26 (1H, d, J 10.7 Hz), 5.86 (1H, d, J 9.9Hz), 6.67 (1H, dd, J 17.4, 10.7 Hz), 7.20 (1H, d, J 8.9 Hz), 8.09 (1H,s), 8.12 (1H, dd, J 8.9, 2.4 Hz); 8.33 (1H, d, J 2.4 Hz); MS(Electrospray) m/z 574 (MNH₄ +); (Found: C, 64.33; H, 7.48; N, 4.68. C₃₀H₄₀ N₂ O₈ requires C, 64.73; H, 7.24; N, 5.03).

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-amino-4-methoxybenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-methoxy-3-nitrobenzoyl)carbamate] (720 mg, 1.29 mmol) wassuspended in ethanol (30 ml). Addition of ethyl acetate (6 ml) broughtabout complete dissolution. Tin (II) chloride (1.26 g, 6.65 mmol) wasadded and the reaction warmed to reflux whilst under an atmosphere ofargon. After 3 hours the reaction was allowed to cool and poured intoethyl acetate and water before neutralising with sodium hydrogencarbonate. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 40% ethyl acetate in hexane.The title compound was isolated as a colourless foam (297 mg, 44%);ν_(max) (CH₂ Cl₂) 3393, 2981, 1773, 1698, 1605 and 1474 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.90 (3H, d, J 6.6 Hz), 0.99 (3H, d, J 6.4 Hz), 1.05-1.55 (12H,m) including 1.21 (3H, s) and 1.34 (3H, s), 1.70-1.79 (2H, m), 1.94-2.08(2H, m), 2.21 (1H, m), 2.53 (1H, dd, J 15.3, 10.0 Hz), 2.92 (1H, q, J6.1 Hz), 3.26 (3H, s), 3.48 (1H, m), 3.93 (3H, s), 3.99 (2H, bs), 5.03(1H, d, J 17.5 Hz), 5.30 (1H, d, J 10.8 Hz), 5.84 (1H, d, J 9.9 Hz),6.73 (1 H, dd, J 17.5, 10.8 Hz), 6.82 (1H, d, J 8.6 Hz), 7.18 (1H, dd, J8.6, 2.3 Hz), 7.23 (1H, d, J 2.3 Hz), 7.90 (1H, s); MS (Electrospray)m/z 527 (MH⁺).

Step 4. Mutilin-14-[N-(3-amino-4-methoxybenzoyl)]-carbamate

The product of Step 3 (100 mg, 0.19 mmol) in dioxane (1 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml) and thereaction stirred at room for 30 minutes. The solution was poured intoethyl acetate and saturated sodium hydrogen carbonate solution. Theaqueous phase was re-extracted with ethyl acetate and the combinedorganic phases were washed with saturated sodium chloride solution. Theorganic phase was dried (MgSO₄) and purified by chromatography on silicagel eluting with 70% ethyl acetate in hexane. The title compound wasisolated as a colourless foam (53 mg, 54%); ν_(max) (CH₂ Cl₂) 3393,2939, 1774, 1733, 1615 and 1476 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80 (3H, d, J6.6 Hz), 0.88 (3H, d, J 7.0 Hz), 1.12-1.80 (16H, m) including 1.19(3H,s) and 1.51 (3H, s), 2.08-2.40 (4H, m), 3.37 (1H, dd, J 11.0, 6.6Hz), 3.91 (3H, s), 3.93 (2H, bs), 5.22 (1H, dd, J 17.4, 1.4 Hz), 5.39(1H, dd, J 10.9, 1.4 Hz), 5.81 (1H, d, J 8.5 Hz), 6.59 (1H, dd, J 17.4,10.9 Hz), 6.89 (1H, d, J 8.4 Hz), 7.11-7.20 (2H, m), 7.80 (1H, bs); MS(Electrospray) m/z 513 (MH⁺).

EXAMPLE 75 Mutilin14-[N-(3-methanesulphonamido-4-methoxybenzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-methanesulphonamido-4-methoxybenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-amino-4-methoxybenzoyl)carbamate] (158 mg, 0.30 mmol) wasdissolved in dichloromethane (5 ml) and treated with pyridine (81 ul,1.05 mmol) followed by methanesulphonyl chloride (81 ul, 1.05 mmol).After stirring for 3 hours, the reaction mixture was diluted withdichloromethane and washed successively with 0.5M hydrochloric acid,saturated aqueous sodium hydrogen carbonate, water and brine. Theorganic phase was dried over magnesium sulphate and concentrated invacuo. The residue was purified by chromatography eluting with 70% ethylacetate in hexane to yield a colourless foam (159 mg, 88%); ν_(max) (CH₂Cl₂) 3338, 2981, 1775, 1697, 1607 and 1476 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90(3H, d, J 6.8 Hz), 1.02 (3H, d, J 6.4 Hz), 1.05-1.59 (12H, m) including1.20 (3H, s) and 1.31 (3H, s), 1.70-1.78 (2H, m), 1.96-2.07 (2H, m),2.22 (1H, m), 2.55(1H, dd, J 15.2, 10.1 Hz), 2.91 (1H, q, J 6.4 Hz),3.02 (3H, s), 3.23 (3H, s), 3.48 (1H, m), 3.99 (3H, s), 5.01 (1H, d, J17.5 Hz), 5.30 (1H, d, J 10.8 Hz), 5.83 (1H, d, J 9.9 Hz), 6.72 (1H, dd,J 17.5, 10.8 Hz), 6.86 (1H, bs), 7.02 (1H, d, J 8.6 Hz), 7.72 (1H, dd, J8.6, 2.2 Hz), 7.93 (1H, d, J 2.2 Hz), 7.99 (1H, s).

Step 2.Mutilin-14-[N-(3-methanesulphonamido-4-methoxybenzoyl)]-carbamate

The product of Step 1 (128 mg, 0.21 mmol) in dioxane (1 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml) and thereaction stirred at room for 30 minutes. The solution was poured intoethyl acetate and saturated sodium hydrogen carbonate solution. Theaqueous phase was re-extracted with ethyl acetate and the combinedorganic phases were washed with saturated sodium chloride solution. Theorganic phase was dried (MgSO₄) and purified by chromatography on silicagel eluting with 70% ethyl acetate in hexane. The title compound wasisolated as a colourless foam (46 mg, 37%); ν_(max) (CH₂ Cl₂) 3340,2941, 1776, 1733, 1607 and 1477 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.81 (3H, d, J6.6 Hz), 0.89 (3H, d, J 6.9 Hz), 1.10-1.82 (16H, m) including 1.21 (3H,s) and 1.52 (3H, s), 2.10-2.38 (4H, m), 2.99 (3H, s), 3.38 (1H, dd, J10.8, 6.5 Hz), 3.96 (3H, s), 5.22 (1H, dd, J 17.4, 1.4 Hz), 5.38 (1H,dd, J 11.1, 1.4 Hz), 5.82 (1H, d, J 8.4 Hz), 6.54 (1H, dd, J 17.4, 11. 1Hz), 6.84 (1H, bs), 6.99 (1H, d, J 8.6 Hz), 7.70 (1H, dd, J 8.6, 2.3Hz), 7.88 (1H, d, J 2.3 Hz), 7.95 (1H, bs).

EXAMPLE 76 Mutilin 14-[N-(isoxazol-5-oyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(isoxazol-5-oyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (633 mg, 1.89 mmol)was combined with isoxazole-5-carbonyl chloride (1.0 g, 7.60 mmol),silver cyanate (1.22 g, 8.14 mmol) and tetrakis(triphenylphosphine)palladium (0) (32 mg) in dry dichloromethane (15 ml) and the reactionstirred at room temperature for 30 minutes in subdued light and under anatmosphere of argon. The mixture was filtered through Kieselguhr and thefiltrate washed with saturated aqueous sodium hydrogen carbonate (×2)and brine. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 30% ethyl acetate in hexane.The title compound was isolated as a colourless foam (850 mg, 95%);ν_(max) (CH₂ Cl₂) 3393, 2929, 1783, 1726, 1597 and 1496 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.88 (3H, d, J 6.8 Hz), 1.01 (3H, d, J 6.4 Hz), 1.08-1.59 (12H,m) including 1.20 (3H, s) and 1.31 (3H, s), 1.69-1.77 (2H, m), 1.93-2.07(2H, m), 2.21 (1H, m), 2.56 (1H, dd, J 15.3, 10.1 Hz), 2.89 (1H, q, J6.3 Hz), 3.22 (3H, s), 3.48 (1H, m), 5.02 (1H, d, J 17.5 Hz), 5.31 (1H,d, J 10.7 Hz), 5.86 (1H, d, J 10.0 Hz), 6.68 (1H, dd, J 17.5, 10.7 Hz),7.03 (1H, d, J 1.8 Hz), 8.39 (1H, bs), 8.43 (1H, d, J 1.8 Hz); MS(CI)m/z 490 (MNH₄ ⁺).

Step 2. Mutilin-14-[N-(isoxazol-5-oyl)]-carbamate

The product of Step 1 (810 mg, 1.71 mmol) in dioxane (6 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (3 ml) and thereaction stirred at room for 30 minutes. The solution was poured intoethyl acetate and saturated sodium hydrogen carbonate solution. Theaqueous phase was re-extracted with ethyl acetate and the combinedorganic phases were washed with saturated sodium chloride solution. Theorganic phase was dried (MgSO₄) and purified by chromatography on silicagel eluting with 50% ethyl acetate in hexane to yield the title compound(540 mg, 69%); ν_(max) (CH₂ Cl₂) 3395, 2959, 1785, 1731 and 1496 cm⁻¹ ;¹ H NMR (CDCl₃) 0.79 (3H, d, J 6.8 Hz), 0.90 (3H, d, J 7.0 Hz),1.10-1.83 (16H, m) including 1.20 (3H, s) and 1.50 (3H, s), 2.10-2.37(4H, m), 3.38 (1H, dd, J 10.8, 6.6 Hz), 5.23 (1H, dd, J 17.3, 1.4 Hz),5.40 (1H, dd, J 10.9, 1.4 Hz), 5.85 (1H, d, J 8.5 Hz), 6.53 (1H, dd, J17.3, 10.9 Hz), 7.10 (1H, d, J 1.9 Hz), 8.36 (1H, bs), 8.41 (1H, d, J1.9 Hz); MS(CI) m/z 476 (MNH₄ ⁺).

EXAMPLE 77 Mutilin 14-[N-(methoxyacetyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(methoxyacetyl)]-carbamate

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg, 1.50 mmol)was combined with methoxyacetyl chloride (547 ul, 6.0 mmol) and silvercyanate (965 mg, 6.40 mmol) in dry dichloromethane (15 ml) and thereaction stirred at room temperature for 10 minutes in subdued light andunder an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 30% ethylacetate in hexane. The title compound was isolated as a colourless foam(630 mg, 94%); ν_(max) (CH₂ Cl₂) 3388, 2932, 1786, 1722 and 1488 cm⁻¹ ;¹ H NMR (CDCl₃) 0.85 (3H, d, J 6.9 Hz), 1.00 (3H, d, J 6.4 Hz),1.08-1.58 (12H, m) including 1.19 (3H, s) and 1.28 (3H, s), 1.64-1.77(2H, m), 1.94-2.06 (2H, m), 2.21 (1H, m), 2.51 (1H, dd, J 15.3, 10.1Hz), 2.88 (1H, q, J 6.4 Hz), 3.21 (3H, s), 3.42 (1H, m), 3.49 (3H, s),4.08 (2H, s), 5.01 (1H, d, J 17.6 Hz), 5.30 (1H, d, J 10.7 Hz), 5.77(1H, d, J 10.0 Hz), 6.69 (1H, dd, J 17.6, 10.7 Hz), 8.26 (1H, bs).

Step 2. Mutilin-14-[N-(methoxyacetyl)]-carbamate

The product of Step 1 (600 mg, 1.34 mmol) in dioxane (6 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (3 ml) and thereaction stirred at room for 2 hours. The solution was poured into ethylacetate and saturated sodium hydrogen carbonate solution. The aqueousphase was re-extracted with ethyl acetate and the combined organicphases were washed with saturated sodium chloride solution. The organicphase was dried (MgSO₄) and purified by chromatography on silica geleluting with 40% ethyl acetate in hexane to yield the title compound asa colourless foam (210 mg, 36%); ν_(max) (CH₂ Cl₂) 3388, 2941, 1787,1726 and 1488 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.74 (3H, d, J 6.7 Hz), 0.90 (3H,d, J 7.0 Hz), 1.10-1.85 (16H, m) including 1.17 (3H, s) and 1.48 (3H,s), 2.04-2.37 (4H, m), 3.35 (1H, dd, J 10.9, 6.6 Hz), 3.45 (3H, s), 4.06(2H, s), 5.22 (1H, dd, J 17.4, 1.5 Hz), 5.38 (1H, dd, J 1.0, 1.5 Hz),5.75 (1H, d, J 8.5 Hz), 6.52 (1H, dd, J 17.4, 11.0 Hz), 8.20 (1H, bs);MS(CI) m/z 453 (MNH₄ ⁺).

EXAMPLE 78 Mutilin 14-[N-(6-methoxynicotinoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(6-methoxynicotinoyl)carbamate]

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg, 1.50 mmol)was combined with 6-methoxynicotinoyl chloride (430 mg, 2.5 mmol) andsilver cyanate (400 mg, 2.67 mmol) in dry dichloromethane (20 ml) andthe reaction stirred at room temperature for 4.5 hours in subdued lightand under an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 30% ethylacetate in hexane. The title compound was isolated as a colourless foam(750 mg, 98%); ν_(max) (CH₂ Cl₂) 3423, 2930, 1776, 1729, 1603 and 1477cm⁻¹ ; ¹ H NMR (CDCl₃) 0.91 (3H, d, J 6.8 Hz), 1.01 (3H, d, J 6.4 Hz),1.10-1.59 (12H, m) including 1.27 (3H, s) and 1.36 (3H, s), 1.68-1.78(2H, m), 1.96-2.04 (2H, m), 2.21 (1H, m), 2.52 (1H, dd, J 15.3, 10.1Hz), 2.91 (1H, q, J 6.4 Hz), 3.23 (3H, s), 3.49 (1H, m), 4.02 (3H, s),5.03 (1H, d, J 17.4 Hz), 5.30 (1H, d, J 10.8 Hz), 5.84 (1H, d, J 10.0Hz), 6.69 (1H, dd, J 17.4, 10.8 Hz), 6.83 (1H, d, J 8.8 Hz), 7.91 (1H,bs), 8.05 (1H, dd, J 8.8, 2.6 Hz), 8.63 (1H, d, J 2.6 Hz); MS(CI) m/z513 (MH⁺).

Step 2. Mutilin-14-[N-(6-methoxynicotinoyl)]-carbamate

The product of Step 1 (720 mg, 1.41 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (3 ml) and thereaction stirred at room for 2 hours. The solution was poured into ethylacetate and saturated sodium hydrogen carbonate solution. The aqueousphase was re-extracted with ethyl acetate and the combined organicphases were washed with saturated sodium chloride solution. The organicphase was dried (MgSO₄) and purified by chromatography on silica geleluting with 50% ethyl acetate in hexane to yield the title compound asa colourless foam (600 mg, 85%); ν_(max) (CH₂ Cl₂) 3423, 2949, 1777,1733, 1603 and 1475 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.82 (3H, d, J 6.7 Hz), 0.89(3H, d, J 7.0 Hz), 1.10-1.82 (16H, m) including 1.20 (3H, s) and 1.49(3H, s), 2.06-2.37 (4H, m), 3.36 (1H, dd, J 10.9, 6.5 Hz), 3.99 (3H, s),5.24 (1H, dd, J 17.4, 1.4 Hz), 5.39 (1H, dd, J 11.0, 1.4 Hz), 5.82 (1H,d, J 8.5 Hz), 6.54 (1H, dd, J 17.4, 11.0 Hz), 6.81 (1H, d, J 8.8 Hz),7.92 (1H, bs), 8.01 (1H, dd, J 8.8, 2.5 Hz), 8.62 (1H, d, J 2.5 Hz);MS(CI) m/z 499 (MH⁺).

EXAMPLE 79 Mutilin 14-[N-(pyrazin 2-oyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(pyrazin-2-oyl)carbamate]

(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg, 1.50 mmol)was combined with pyrazin-2-oyl chloride (1.14 g, 8.0 mmol) and silvercyanate (1.20 g, 8.0 mmol) in dry dichloromethane (15 ml) and thereaction stirred at room temperature for 10 minutes in subdued light andunder an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 40% ethylacetate in hexane. The title compound was isolated as a colourless foam(498 mg, 69%); ν_(max) (CH₂ Cl₂) 3364, 2931, 1781, 1720, 1697 and 1490cm⁻¹ ; ¹ H NMR (CDCl₃) 0.90 (3H, d, J 6.8 Hz), 1.01 (3H, d, J 6.4 Hz),1.09-1.61 (12H, m) including 1.20 (3H, s) and 1.38 (3H, s), 1.69-1.79(2H, m), 1.94-2.06 (2H, m), 2.21 (1H, m), 2.56 (1H, dd, J 15.3, 10.1Hz), 2.92 (1H, q, J 6.4 Hz), 3.24 (3H, s), 3.50 (1H, m), 5.03 (1H, d, J17.4 Hz), 5.32 (1H, d, J 10.7 Hz), 5.89 (1H, d, J 9.9 Hz), 6.75 (1H, dd,J 17.4, 10.7 Hz), 8.62 (1H, d, J 2.5 Hz), 8.88 (1H, d, J 2.5 Hz), 9.51(1H, d, J 1.5 Hz), 9.76 (1H, bs).

Step 2. Mutilin-14-[N-(pyrazin-2-oyl)]-carbamate

The product of Step 1 (450 mg, 0.93 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room for 1 hour. The solution was poured into ethylacetate and saturated sodium hydrogen carbonate solution. The aqueousphase was re-extracted with ethyl acetate and the combined organicphases were washed with saturated sodium chloride solution. The organicphase was dried (MgSO₄) and purified by chromatography on silica geleluting with 50% ethyl acetate in hexane to yield the title compound asa colourless foam (420 mg, 96%); ν_(max) (CH₂ Cl₂) 3364, 2939, 1782,1734 and 1491 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.79 (3H, d, J 6.7 Hz), 0.91 (3H,d, J 7.0 Hz), 1.10-1.85 (16H, m) including 1.20 (3H, s) and 1.58 (3H,s), 2.10-2.43 (4H, m), 3.39 (1H, dd, J 10.9, 6.6 Hz), 5.24 (1H, dd, J17.4, 1.5 Hz), 5.40 (1H, dd, J 10.9, 1.4 Hz), 5.85 (1H, d, J 8.5 Hz),6.59 (1H, dd, J 17.4, 10.9 Hz), 8.60 (1H, d, J 2.3 Hz), 8.84 (1H, d, J2.5 Hz), 9.45 (1H, d, J 2.3 Hz), 9.72 (1H, bs); MS(CI) m/z 487 (MNH₄ ⁺).

EXAMPLE 80 Mutilin 14-(N-thiophen-2-oyl)-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-thiophen-2-oyl)-carbamate

A suspension of silver cyanate in dichloromethane (10 ml) was treatedwith 2-thiophene carbonyl chloride and the mixture heated under refluxfor 45 mins. IR analysis showed no starting material. The reactionmixture was cooled and filtered through Kieselguhr affording a paleyellow solution. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin(0.5 g) was added to the solution. After 20 mins. the solution waswashed with dilute hydrochloric acid, saturated sodium chloride and thendried over anhydrous magnesium sulphate. Removal of solvent in vacuoafforded the product as a white solid which was purified by silica gelchromatography eluting with dichloromethane then 1% and 2%acetone/dichloromethane to give the title compound as a white solid(0.686 g, 94%); ν_(max) (CH₂ Cl₂) 3422, 1773, 1726(w), 1698, 1521 and1481 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.89 (3H, d, J6.8 Hz), 1.01 (3H, d, J6.4Hz), 1.07-1.78 (8H, m), 1.20 (3H, s), 1.34 (3H, s), 1.99 (2H, m), 2.21(1H,m), 2.55 (1H, dd, J10.1,15.3 Hz), 2.90 (1H, q, J6.4 Hz), 3.22 (3H,s), 3.46 (1H, m), 5.01 (1H, d, J17.5), 5.28 (1H, d, J10.7 Hz), 5.86 (1H,d, J10.0 Hz), 6.70 (1H, d, J10.7,17.5 Hz), 7.13 (1H, m), 7.66 (2H, m)and 8.03 (1H, s); MS (NH₃ DCI) m/z 488 (MH⁺) and 505 (MNH₄ ⁺).

Step 2. Mutilin 14-(N-thiophen-2-oyl)-carbamate

The product from Step 1 (0.45 g) in dioxan (1.5 ml) was treated withLukas reagent (sat. ZnCl₂ /conc. HCl; 1.5 ml), at room temperature. Thereaction mixture darkened and became warm. After 5 min. t.l.c. analysisshowed no starting material. The reaction mixture was diluted with ethylacetate and the solution washed with water. The organic phase wasextracted with ethyl acetate and the combined organic extracts washedwith saturated sodium hydrogen carbonate, saturated sodium chloride,dried and concentrated to an orange gum. Silica gel chromatographyeluting with ethyl acetate/hexane gave the product as a white solid,(0.173 g, 40%); ν_(max) (CH₂ Cl₂) 3564, 3424, 1775, 1733, 1705, 1521 and1482 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80 (3H, d, J6.7 Hz), 0.89 (3H, d, 7.0 Hz),1.14 (1H, m), 1.19 (3H, s), 1.37-1.82 (9H, m), 1.54 (3H, s), 2.12-2.37(4H, m), 3.37 (1H, dd, J6.6,10.6 Hz), 5.23 (1h, dd, J1.5,17.4 Hz), 5.36(1H, dd, J1.5,11.1 Hz), 5.83 (1H, d, J8.5 Hz), 6.54 (1H, J, 11.0,17.4Hz), 7.12 (1H, m), 7.63 (2H, m) and 7.95 (1H, s); MS (NH₃ DCI) m/z 474(MH⁺) and 491 (MNH₄ ⁺).

EXAMPLE 81 Mutilin 14-[(S)-Tetrahydrofuran-2-oyl]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[(S)-tetrahydrofuran-2-oyl]-carbamate

(S)-(-)-Tetrahydrofuroic acid (0.464 g) in dichloromethane (3 ml) atroom temperature was treated with oxalyl chloride (0.635 g) and one dropof DMF for 1 h. IR analysis showed complete conversion to the acidchloride. The solvent and excess oxalyl chloride were removed in vacuoand the residue redissolved in dry dichloromethane.

The acid chloride was reacted with silver cyanate (0.645 g) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.322 g) aspreviously described in Example 80, Step 1. Following purification bysilica gel chromatography the product was isolated as a colourless foam,(0.43 g, 91%); ν_(max) (CH₂ Cl₂) 3381, 1783, 1744, 1717 and 1698 cm⁻¹ ;¹ H NMR (CDCl₃) 0.83 (3H, d, J6.9 Hz), 0.99 (3H, d, J6.4 Hz), 1.06-1.75(9H, m), 1.19 (3H, s), 1.29 (3H, s), 1.87-2.38 (7H, m), 2.50 (1H, dd,J10.1,15.3 Hz), 2.88 (1H, q, J6.4 Hz), 3.22 (3H, s), 3.46 (1H, m), 3.96(2H, m), 4.43 (1H, dd, J5.7,8.4 Hz), 5.00 (1H, d, J17.4 Hz), 5.29 (1H,d, J10.7 Hz), 6.71 (1H, dd, J10.7,17.5 Hz) and 8.59 (1H, s); MS (NH4DCI) m/z 494 (MNH₄ ⁺).

Step 2. Mutilin 14-[(S)-tetrahydrofuran-2-oyl]-carbamate

The product from Step 1, (0.388 g) in dioxan (1 ml) was treated withLukas reagent as described in Example 80, Step 2. After purification bysilica gel chromatography the product was isolated as a colourless foam,(0.242 g, 64%); ν_(max) (CH₂ Cl₂) 3562, 3381, 1784, 1733 and 1480 cm⁻¹ ;¹ H NMR (CDCl₃) 0.75 (3H, d, J6.7 Hz), 0.89 (3H, d, J7.1 Hz), 1.15 (1H,m), 1.18 (3H, s), 1.42-2.35 (19H, m), 1.50 (3H, s), 3.36 (1H, dd,J6.7,10.9 Hz), 3.94 (2H, m), 4.40 (1H, dd, J5.8,8.4 Hz), 5.22 (1H, dd,J1.5,17.4 Hz), 5.37 (1H, dd, J1.5,10.9 Hz), 5.77 (1H, d, J8.5 Hz), 6.54(1H, dd, J11.0(,17.4 Hz) and 8.51 (1H, s); MS (NH₄ DCI) m/z 479 (MNH₄⁺).

EXAMPLE 82 Mutilin 14-[(R)-Tetrahydrofuran-2-oyl]carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[(R)-tetrahydrofuran-2-oylcarbamate]

(R)-(+)-Tetrahydrofuroic acid (0.464 g) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.322 g) wereconverted into the title compound as described in Example 80, Step 1.Following purification by silica gel chromatography the title compoundwas obtained as a colourless foam (0.432 g, 91%); ν_(max) (CH₂ Cl₂)3383, 1782, 1718, 1698 and 1474 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.86 (3H, d, J6.9Hz), 1.00 (3H, d, J6.4 Hz), 1.06-1.75 (9H, m), 1.17 (3H, s), 1.28 (3H,s), 1.87-2.38 (7H, m), 2.50 (1H, dd, J10.1,15.3 Hz), 2.88 (1H, q, J6.4Hz), 3.22 (3H, s), 3.46 (1H, m), 3.88-4.06 (2H, m), 4.43 (1H, dd,J5.7,8.4 Hz), 5.00 (1H, d, J17.4 Hz), 5.29 (1H, d, J10.7 Hz), 6.71 (1H,dd, J10.7,17.5 Hz) and 8.59 (1H, s); MS (NH3 DCI) m/z 494 (MNH₄ ⁺).

Step 2. Mutilin 14-[(R)-tetrahydrofuran-2-oyl]-carbamate

The product from Step 1 (0.38 g) in dioxan (1 ml) was treated with Lukasreagent as described in Example 80, Step 2. After purification by silicagel chromatography the product was isolated as a colourless foam (0.195g, 53%); ν_(max) (CH₂ Cl₂) 3560, 3382, 1783, 1733 and 1480 cm⁻¹ ; ¹ HNMR (CDCl₃) 0.76 (3H, d, J6.7 Hz), 0.88 (3H, d, J7.1 Hz), 1.15 (1H, m),1.18 (3H, s), 1.42-2.35 (19H, m), 1.48 (3H, s), 3.36 (1H, dd, J6.7,10.9Hz), 3.86-4.05 (2H, m), 4.40 (1H, dd, J5.8,8.4 Hz), 5.22 (1H, dd,J1.5,17.4 Hz), 5.37 (1H, dd, J1.5,10.9 Hz), 5.77 (1H, d, J8.5 Hz), 6.54(1H, dd, J 11.0,17.4 Hz) and 8.51 (1H, s); MS (NH₄ DCI) m/z 479 (MNH₄⁺).

EXAMPLE 83 Mutilin 14-[N-(2,4-Difluorobenzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2,4-difluorobenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (200 mg),2,4-difluoro-benzoyl chloride (212 mg), and silver cyanate (180 mg) indichloromethane (5 ml) were stirred at room temperature for 2 hours. Themixture was diluted with ethyl acetate (100 ml) and filtered. Thefiltrate was washed with water (2×30 ml) and saturated sodiumbicarbonate solution (30 ml), the solution was dried (sodium sulphate),and the solvent was evaporated under reduced pressure to give the titlecompound as a colourless gum (400 mg); ¹ H NMR (CDCl₃) inter alia 3.23(3H, s), 3.46 (1H, m), 5.00 (1H, d, J 17.5 Hz), 5.30 (1H, d, J 10.5 Hz),5.81 (1H, d, J 10 Hz), 6.72 (1H, dd, J 17.5, 10.5 Hz), 6.90 (1H, m),7.03 (1H, m), 8.10 (1H, m), 8.40 (1H, d, J 13 Hz).

Step 2. Mutilin 14-[N-(2,4-Difluorobenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo4-epi-mutilin14-[N-(2,4-difluoro-benzoyl)]-carbamate from Step 1 (400 mg) in1,4-dioxane (5 ml) was treated with a saturated solution of zincchloride in conc. HCl (2 ml) and the solution was kept at roomtemperature for 3 hours. The solution was diluted with ethyl acetate (50ml) and washed with water (2×30 ml) and saturated sodium bicarbonatesolution (30 ml). The solution was dried (sodium sulphate) and thesolvent was evaporated under reduced pressure to give a pale yellow gum.The gum was chromatographed on silica gel using gradient elution from1:4 to 2:3 ethyl acetate/hexane, to give the title compound as a whitefoam. Crystallisation from dichloromethane/hexane gave colourlesscrystals (250 mg), m.p. 178-180° C.; ¹ H NMR (CDCl₃) inter alia 3.37(1H, dd, J 11, 6.6 Hz), 5.23 (1H, dd, J 17.3, 1.4 Hz), 5.38 (1H, dd, J11, 1.4 Hz), 5.80 (1H, d, J 8.5 Hz), 6.55 (1H, dd, J 17.3, 11 Hz), 6.91(1H, m), 7.03 (1H, m), 8.10 (1H, m), 8.30 (1H, d, J 13 Hz).

EXAMPLE 84 Mutilin 14-[N-(3,4-Difluorobenzoyl)]-carbamate

Using the methods described in Example 83,(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (250 mg) and3,4-difluorobenzoyl chloride (210 mg) were converted into(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo4epi-mutilin14-[N-(3,4-difluorobenzoyl)]-carbamate [MS(EI) m/z 517 (M⁺)], and henceinto the title compound, which was obtained as colourless crystals (120mg), m.p. 144-146° C. (dichloromethane/hexane); ¹ H NMR (CDCl₃) interalia 3.37 (1H, dd, J 10.7, 6.6 Hz), 5.23 (1H, dd, J 17.3, 1.4 Hz), 5.32(1H, dd, J 11, 1.3 Hz), 5.82 (1H, d, J 8.5 Hz), 6.50 (1H, dd, J 17.3, 11Hz), 7.30 (1H, m), 7.60 (1H, m), 7.70 (1H, m), 8.13 (1H, s).

EXAMPLE 85 Mutilin14-[N-(1-tert-butyloxycarbonyl-azetidin-3-oyl)]-carbamate

Step 1. 1-tert-Butyloxycarbonyl-azetidine-3-carboxylic acid

3-Azetidine carboxylic acid (250 mg) in water (2 ml) was treated with asolution of di-tert-butyl dicarbonate (650 mg) in 1,4-dioxane (3 ml) andthe mixture was stirred at room temperature for 17 hours. The mixturewas acidified by adding a few drops of 1M HCl, was diluted with water(10 ml), and extracted with ethyl acetate (2×20 ml). The organic extractwas washed with water (2×10 ml). The solution was dried (sodiumsulphate) and the solvent was evaporated under reduced pressure to givea colourless gum. Crystallisation from diethyl ether/pentane gave thetitle compound as colourless crystals (470 mg), m.p. 102.5-104° C.; ¹ HNMR (CDCl₃) 1.44 (9H, s), 3.38 (1H, quin, J 7.4 Hz), 4.13 (4H, d, J 7.4Hz).

Step 2. Mutilin 11-trifluoroacetate

Mutilin (960 mg) in dry tetrahydrofuran (12 ml) was treated withpyridine (0.3 ml) and the solution was cooled to 0° C. Trifluoroaceticanhydride (0.48 ml) was added dropwise over 3 minutes to the stirredsolution. The solution was kept at 0° C. for 2 hours, and was thendiluted with ethyl acetate (100 ml) and washed with water (2×30 ml),sodium bicarbonate solution (30 ml), and saturated sodium chloridesolution (30 ml). The solution was dried (sodium sulphate) and thesolvent was evaporated under reduced pressure to give a colourless gum.The gum was chromatographed on silca gel using 1:9 to 1:4 ethylacetate/hexane to give the title compound as colourless crystals (570mg). Recrystallisation from dichloromethane/hexane gave colourless rods,m.p. 170-171° C.; ν_(max) (CHCl₃) 3636, 1777, and 1736 cm⁻¹ ; MS(EI) m/z416 (M⁺).

Step 3. Mutilin14-[N-(1-tert-butyloxycarbonyl-azetidin-3-oyl)]-carbamate11-trifluoroacetate

1-tert-Butyloxycarbonyl-azetidine-3-carboxylic acid (345 mg) in drydichloromethane (10 ml) was treated with oxalyl chloride (254 mg; 0.175ml) and N,N-dimethylformamide (1 drop). The solution was stirred for 1.5hours, and then the solvent was removed by evaporation under reducedpressure. The residue was dissolved in toluene (10 ml), and the toluenewas evaporation under reduced pressure to give1-tert-butyloxycarbonyl-azetidine-3-carbonyl chloride as a colourlessoil. The oil was dissolved in dichloromethane (6 ml) and the solutionwas treated with silver cyanate (525 mg). The mixture was stirred for 10minutes, and then mutilin 11-trifluoroacetate (535 mg) indichloromethane (9 ml) was added. The mixture was stirred for 20 hours.Ethyl acetate (50 ml) was added and the mixture was filtered. Thefiltrate was washed with saturated sodium bicarbonate solution (20 ml)and saturated sodium chloride solution (20 ml). The solution was dried(sodium sulphate) and the solvent was removed under reduced pressure toyield a colourless gum. The gum was chromatographed on silica gel using1:4 to 1:2 ethyl acetate/hexane to give the title compound as acolourless gum (485 mg); ¹ H NMR (CDCl₃) inter alia 1.43 (9H, s), 3.93(1H, quin, J 7.2 Hz), 4.98 (1H, d, J 6.9 Hz), 4.14 (4H, m), 5.23 (1H, d,J 17.5 Hz), 5.29 (1H, d, J 11.2 Hz), 5.58 (1H, d, J 8 Hz), 6.31 (1H, dd,J 17.5, 11.2 Hz), 7.57 (1H, s).

Step 4. Mutilin14-[N-(1-tert-butyloxycarbonyl-azetidin-3-oyl)]-carbamate

Mutilin 14-[N-(1-tert-butyloxycarbonyl-azetidin-3-oyl)]-carbamate11-trifluoroacetate (450 mg) was dissolved in tetrahydrofuran (10ml)/water (2 ml) and the solution was treated with 0.5M sodium hydroxide(1.5 ml). The mixture was stirred for 4.5 hours, and was then dilutedwith ethyl acetate (50 ml) and washed with water (2×30 ml). The solutionwas dried (sodium sulphate) and the solvent was removed by evaporationunder reduced pressure to give the title compound as a white foam (380mg); ν_(max) (CHCl₃) 3551, 3396, and 1706 cm⁻¹ ; ¹ H NMR (CDCl₃) interalia 1.43 (9H, s), 3.35 (1H, m), 3.94 (1H, quin, J7.5 Hz), 4.10 (4H, m),5.22 (1H, d, J 17.3 Hz), 5.35 (1H, d, J 11 Hz), 5.65 (1H, d, J 8.4 Hz),6.42 (1H, dd, J 17.3, 11 Hz), 7.26 (1H,s).

EXAMPLE 86 Mutilin 14-(N-azetidin-3-oyl)-carbamate

Mutilin 14-[N-(1-tert-butyloxycarbonyl-azetidin-3-oyl)]-carbamate (350mg) in dichloromethane (8 ml) was treated with trifluoroacetic acid (0.5ml) and the solution was kept at room temperature for 5 hours. Thesolvent was removed under reduced pressure and the residue was dissolvedin ethyl acetate (20 ml). The solution was extracted with dilute HCl (10ml), and the extract was washed with ethyl acetate (10 ml). The aqueoussolution was basified (pH 10) using potassium carbonate, and was thenextracted with ethyl acetate (3×10 ml). The organic extract was washedwith saturated sodium chloride and dried (sodium sulphate). The solventwas removed under reduced pressure to give a white waxy solid (125 mg).The solid was chromatographed on silca gel using 1:9:90 ammonia solution(35%)/methanol/dichloromethane to give the title compound as a whitefoam (100 mg); ¹ H NMR (1:9 CD₃ OD:CDCl₃) inter alia 3.33 (1H, d, J 6.3Hz), 4.01 (4H, m), 5.20 (1H, d, J 17.4 Hz), 5.32 (1H, d, J 11.2 Hz),5.64 (1H, d, J 8.3 Hz), 6.41 (1H, dd, J 17.4, 11.2 Hz); MS(ES) m/z 447(MH⁺).

EXAMPLE 87 Mutilin 14-[N-(1-ethyl-piperidin-4-oyl)]-carbamate

Step 1. Ethyl 1-ethyl-isonipecotate

Ethyl isonipecotate (6.28 g) in ethanol (35 ml) was treated with ethyliodide (6.86 g) and powdered potassium carbonate (10 g). The mixture wasstirred and heated under reflux for 20 hours. The mixture was cooled toroom temperature and the solid was removed by filtration and was washedwith ethanol (2×10 ml). The ethanol was removed from the filtrate byevaporation under reduced pressure, and the resulting residue waspartitioned between chloroform (100 ml) and water (50 ml). The organiclayer was separated, washed with saturated sodium chloride solution, anddried (sodium sulphate). The solvent was removed by evaporation underreduced pressure to give the title compound as a yellow oil (6.62 g);MS(EI) m/z 185 (M⁺).

Step 2. 1-Ethyl-isonipecotic Acid Hydrochloride

Ethyl 1-ethyl-isonipecotate (5.5 g) was dissolved in water (22 ml)/c.HCl(39 ml) and the solution was heated under reflux for 4 hours. Thesolvent was removed by evaporation under reduced pressure. The residuewas dissolved in water (30 ml), and the water was removed by evaporationunder reduced pressure. The residue was triturated with toluene (50 ml),and the toluene was removed by evaporation under reduced pressure togive a solid which was dried in vacuo for 18 hours. The title compoundwas thus obtained as a white powder (5.4 g); MS(EI) m/z 157 (M⁺).

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-ethyl-piperidin-4-oyl)]-carbamate

1-Ethyl-isonipecotic acid hydrochloride (0.95 g) was suspended inthionyl chloride (8 ml) and the mixture was stirred and heated underreflux for 3 hours to give a clear yellow solution. The thionyl chloridewas removed by evaporation under reduced pressure and the resultingresidue was suspended in toluene (5 ml) and the toluene was removed byevaporation under reduced pressure to give 1-ethyl-isonipecotoylchloride hydrochloride as a white solid. The acid chloride was suspendedin dry dichloromethane (20 ml) and silver cyanate (1.5 g) was added. Themixture was stirred and heated under reflux for 1 hour. The mixture wascooled to room temperature and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1 g) andtriethylamine (0.5 g) were added. The mixture was stirred at roomtemperature for 16 hours. The mixture was diluted with ethyl acetate (50ml) and the solid was removed by filtration. The filtrate was washedwith saturated sodium bicarbonate and saturated sodium chloride. Thesolution was dried (sodium sulphate), and the solvent was removed byevaporation under reduced pressure to give a yellow gum. The gum waschromatographed on silica gel using 1:3 ethyl acetate/chloroform and1:9:90 ammonia solution (35%)/methanol/dichloromethane to give the titlecompound as a colourless gum (134 mg); ¹ H NMR (CDCl₃) inter alia 2.88(2H, q, J 6.5 Hz), 3.08 (3H, m), 3.22 (3H, s), 3.42 (1H, m), 5.04 (1H,d, J 17.5 Hz), 5.33 (1H, d, J 10.7 Hz), 5.74 (1H, d, J 9.9 Hz), 6.63(1H, dd, J 17.5, 10.7 Hz), 7.47 (1H, s).

Step 4. Mutilin 14-[N-(1-ethyl-piperidin-4-oyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-ethyl-piperidin-4-oyl)]-carbamate (110 mg) in 1,4-dioxane (0.7ml) was treated with c.HCl (0.7 ml) and the solution was kept at roomtemperature for 2.5 hours. The solution was diluted with water (10 ml)and washed with dichloromethane (10 ml). The aqueous phase was basifiedby careful addition of solid potassium carbonate and the resultingmixture (pH 10) was extracted with chloroform (3×10 ml). The organicextract was dried (sodium sulphate) and the solvent was removed byevaporation under reduced pressure to give the title compound as a whitesolid (80 mg); ¹ H NMR (CDCl₃) inter alia 1.12 (3H, t, J 7.1 Hz), 2.48(2H, q, J 7.1 Hz), 2.97 (3H, m), 3.37 (1H, dd, J 10.3, 6.6 Hz), 5.24(1H, d, J 17.5 Hz), 5.37 (1H, d, J 11 Hz), 5.70 (1H, d, J 8.4 Hz), 6.50(1H, dd, J 17.5, 11 Hz), 7.35 (1H, s); MS(EI) m/z 502 (M⁺).

EXAMPLE 88 Mutilin 14-{N-[1-(1-methyl-ethyl)-piperidin-4-oyl]}-carbamate

Step 1. Ethyl 1-(1-methyl-ethyl)-isonipecotate

Using the process described in Example 87, Step 1, ethyl isonipecotate(6.28 g) and 2-iodo-propane (7.48 g) were converted into the titlecompound, which was obtained as a pale yellow oil (7.17 g); MS(EI) m/z199 (M⁺).

Step 2. 1-(1-Methyl-ethyl)-isonipecotic acid hydrochloride

Using the process described in Example 87, Step 2, ethyl1-(1-methyl-ethyl)-isonipecotate (6 g) was converted into the titlecompound, which was obtained as a white powder (6.1 g); MS(EI) m/z 171(M⁺).

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{-N-[1-(1-methyl-ethyl)-piperidin-4-oyl]}-carbamate

Using the process described in Example 87, Step 3,1-(1-methyl-ethyl)-isonipecotic acid hydrochloride (0.96 g) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1 g) wereconverted into the title compound, which was obtained as a pale yellowgum (195 mg); MS(EI) m/z 530 (M⁺).

Step 4. Mutilin 14-{N-[1-(1-methyl-ethyl)-piperidin-4-oyl]}-carbamate

Using the process described in Example 87, Step 4,(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[1-(1-methyl-ethyl)-piperidin-4oyl]}-carbamate (170 mg) wasconverted into the title compound, which was obtained as a white solid(10 mg); ¹ H NMR (CDCl₃) inter alia 1.01 (6H, d, J 6.5 Hz), 2.74 (1H,m), 2.92 (3H, m), 3.37 (1H, dd, J 10.5, 6.6 Hz), 5.23 (1H, d, J 17.4Hz), 5.36 (1H, d, J 11 Hz), 5.71 (1H, d, J 8.4 Hz), 6.50 (1H, dd, J17.4, 11 Hz), 7.32 (1H, s); MS(EI) m/z 516 (M⁺).

EXAMPLE 89 Mutilin14-{N-[1-(2-methoxy-ethyl)-piperidin-4-oyl]}-carbamate

Step 1. Ethyl 1-(2-methoxy-ethyl)-isonipecotate

Using the process described in Example 87, Step 1, ethyl isonipecotate(6.28 g) and 2-bromoethyl methyl ether (6.12 g) were converted into thetitle compound, which was obtained as a light yellow oil (8.47 g);MS(EI) m/z 216 (MH⁺); Found: 216.1601, C₁₁ H₂₂ NO₃ requires 216.1599.

Step 2. 1-(2-Methoxy-ethyl)-isonipecotic acid hydrochloride

Using the process described in Example 87, Step 2, ethyl1-(2-methoxy-ethyl)-isonipecotate (7.3 g) was converted into the titlecompound, which was obtained as a yellow gum (7.1 g); MS(EI) m/z 187(M⁺).

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[1-(2-methoxy-ethyl)-piperidin-4-oyl]}-carbamate

Using the process described in Example 87, Step 3,1-(2-methoxy-ethyl)-isonipecotic acid hydrochloride (0.98 g) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1 g) wereconverted into the title compound, which was obtained as a pale yellowsolid (80 mg); MS(EI) m/z 546 (M⁺).

Step 4. Mutilin 14-{N-[1-(2-methoxy-ethyl)-piperidin-4-oyl]}-carbamate

Using the process described in Example 87, Step 4,(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[1-(2-methoxy-ethyl)-piperidin-4-oyl]}-carbamate (65 mg) wasconverted into the title compound, which was obtained as a white solid(50 mg); ¹ H NMR (CDCl₃) inter alia 2.58 (2H, t, 5.7 Hz), 3.00 (3H, m),3.36 (4H, s overlapping m), 3.51 (2H, t, J 5.7 Hz), 5.24 (1H, d, J 17.3Hz), 5.37 (1H, d, J 11 Hz), 5.70 (1H, d, J 8.4 Hz), 6.50 (1H, dd, J17.3, 11 Hz), 7.31 (1H, s); MS(EI) m/z 532 (M⁺); Found: 532.3523, C₃₀H₄₈ N₂ O₆ requires 532.3512.

EXAMPLE 90 Mutilin 14-[N-(1-propyl-piperidin-4-oyl)]-carbamate

Step 1. Ethyl 1-propyl-isonipecotate

Using the process described in Example 87, Step 1, ethyl isonipecotate(4.2 g) and propyl iodide (5 g) were converted into the title compound,which was obtained as a light yellow oil (4.39 g); MS(EI) m/z 199 (M⁺).

Step 2. 1-propyl-isonipecotic acid hydrochloride

Using the process described in Example 87, Step 2, ethyl1-propyl-isonipecotate (4.3 g) was converted into the title compound,which was obtained as an off-white solid (4.4 g); MS(EI) m/z 171 (M⁺).

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-propyl-piperidin-4-oyl)]-carbamate

Using the process described in Example 87, Step 3, 1-propyl-isonipecoticacid hydrochloride (0.5 g) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.5 g) wereconverted into the title compound, which was obtained as a colourlessgum (65 mg); MS(EI) m/z 530 (M⁺).

Step 4. Mutilin 14-[N-(1-propyl-piperidin-4-oyl)]-carbamate

Using the process described in Example 87, Step 4,(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-propyl-piperidin-4-oyl)]-carbamate (50 mg) was converted intothe title compound, which was obtained as a white solid (37 mg); ¹ H NMR(CDCl₃) inter alia 3.00 (3H, m), 3.36 (1H, dd, J 10. 6.6 Hz), 5.24 (1H,d, J 17.3 Hz), 5.36 (1H, d, J 11 Hz), 5.70 (1H, d, J 8.6 Hz), 6.48 (1H,dd, J 17.3, 11 Hz), 7.34 (1H, s); MS(EI) m/z 516 (M⁺).

EXAMPLE 91 Mutilin 14-[N-(quinuclidin-4-oyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(quinuclidin-4-oyl)]-carbamate

Using the process described in Example 87, Step 3, quinuclidine4-carboxylic acid hydrochloride (Helvetica Chimica Acta, 1974, 57, 2332)(230 mg) and (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (330mg) were converted into the title compound, which was obtained as awhite foam (160 mg); ¹ H NMR (CDCl₃) inter alia 1.90 (6H, dd, J 8, 7.4Hz), 3.10 (6H, dd, J 8, 7.4 Hz)), 3.21 (3H, s), 5.00 (1H, d, J 17.5 Hz),5.27 (1H, d, J 10.7 Hz), 5.77 (1H, d, J 10 Hz), 6.68 (1H, dd, J 17.5,10.7 Hz), 7.85 (1H, broad s); MS(ES) m/z 515 (MH⁺).

Step 2. Mutilin 14-[N-(quinuclidin-4-oyl)]-carbamate

Using the process described in Example 87, Step 4,(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(quinuclidin-4-oyl)]-carbamate (140 mg) was converted into thetitle compound, which was obtained as a white solid (86 mg); ¹ H NMR(CDCl₃) inter alia 0.73 (3H, d, J 6.7 Hz), 0.87 (3H, d, J 7 Hz), 1.17(3H, s), 1.49 (3H, s), 1.68 (6H, dd, J 8, 7.3 z), 2.93 (6H, dd, J 8, 7.3Hz), 3.34 (1H, dd, J 10, 6.6 Hz), 5.22 (1H, d, J 17.3 Hz), 5.36 (1H, d,J 11 Hz), 5.76 (1H, d, J 8.5 Hz), 6.54 (1H, dd, J 17.3, 11 Hz); MS(ES)m/z 501 (MH⁺).

EXAMPLE 92 Mutilin 14-[N-(quinuclidin-4-oyl)]-carbamate hydrochloride

Mutilin 14-[N-(quinuclidin-4-oyl)]-carbamate (71 mg) was dissolved inethyl acetate (5 ml)/1,4-dioxane (2 ml) and 4M HCl in dioxane (0.2 ml)was added. The solution was concentrated to ca. 1 ml by evaporation ofsolvent under reduced pressure, and toluene (5 ml) was added to give awhite precipitate. The precipitate was collected by filtration, washedwith toluene (2 ml), and dried in vacuo to give the title compound as awhite solid (79 mg); ¹ H NMR (D₂ O) inter alia 0.69 (3H, d, J 6 Hz),0.92 (3H, d, J 6.8 Hz), 1.15 (3H, s), 1.39 (3H, s), 2.16 (6H, dd, J 8.2,7.5 Hz), 3.42 (6H, dd, J 8.2, 7.5 Hz), 3.58 (1H, d, J 6 Hz), 5.20 (1H,d, J 17.5 Hz), 5.28 (1H, d, J 11.1 Hz), 5.68 (1H, d, J 8.1 Hz), 6.36(1H, dd, J 17.5, 11.1 Hz).

EXAMPLE 93 Mutilin 14-{N-(1-azabicyclo[2.2.1]heptan-4-oyl)}-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-(1-azabicyclo[2.2.1]heptan-4-oyl)}-carbamate

Using the process described in Example 87, Step 3, 1-azabicyclo[2.2.1]heptane 4-carboxylic acid hydrochloride (Chemical Abstracts, 1989,110,95016) (700 mg) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1 g) wereconverted into the title compound, which was obtained as a white solid(330 mg); ¹ H NMR (CDCl₃) inter alia 2.05 (4H, m), 2.72 (4H, m), 3.08(2H, m), 3.22 (3H, s), 3.44 (1H, m), 5.02 (1H, d, J 17.5 Hz), 5.30 (1H,d, J 11.6 Hz), 5.80 (1H, d, J 9.9 Hz), 6.69 (1H, dd, J 17.5, 11.6 Hz).7.48 (1H, s); MS(ES) m/z 501 (MH⁺).

Step 2. Mutilin 14-{N-(1-azabicyclo[2.2.1]heptan-4-oyl)}-carbamate

Using the process described in Example 87, Step 4,(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-(1-azabicyclo[2.2.1] heptan-4-oyl)}-carbamate (300 mg) wasconverted into the title compound, which was obtained as a white solid(250 mg); ¹ H NMR (CDCl₃) inter alia 2.28 (4H, m), 3.06 (2H, m), 3.37(1H, broad s), 5.24 (1H, dd, J 17,3, 1.4 Hz), 5.38 (1H, dd, J 11, 1.4Hz), 5.78 (1H, d, J 8.5 Hz), 6.64 (1H, dd, J 17.3, 11 Hz), 7.38 (1H, s);MS(EI) m/z 486 (M⁺); Found: 486.3085, C₂₈ H₄₂ N₂ O₅ requires 486.3094.

EXAMPLE 94 Mutilin 14-[N-(N,N-dimethylcarbamoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(N,N-dimethylcarbamoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (270 mg, 0.80 mmol)was combined with dimethylcarbamoyl chloride (0.088 ml, 0.96 mmol) andsilver cyanate (197 mg, 1.31 mmol) in dry dichloromethane (15 ml) andthe reaction stirred at room temperature for 3 days in subdued light andunder an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 40% ethylacetate in hexane. The title compound was isolated as a colourless foam(135 mg, 38%); ν_(max) (CH₂ Cl₂) 3052, 2981, 1771, 1695, 1490 and 1459cm⁻¹ ; MS(CI) m/z 449 (MH⁺), 466 (MNH₄ ⁺).

Step 2. Mutilin-14-[N-(N,N-dimethylcarbamoyl)]-carbamate

The product of Step 1 (110 mg, 0.25 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml) and thereaction stirred at room temperature for 30 minutes. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 70% ethyl acetate in hexane toyield the title compound (90 mg, 83%); ν_(max) (CH₂ Cl₂) 3402, 2935,1774, 1735, 1686 and 1489 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.78 (3H, d, J 6.6 Hz),0.89 (3H, d, J 7.0 Hz), 1.10-1.83 (16H, m) including 1.19 (3H, s) and1.43 (3H, s), 2.06-2.37 (4H, m), 2.99 (6H, s), 3.37 (1H, dd, J 10.8, 6.7Hz), 5.20 (1H, dd, J 17.3, 1.5 Hz), 5.36 (1H, dd, J 11.1, 1.5 Hz), 5.71(1H, d, J 8.4 Hz), 6.53 (1H, dd, J 17.3, 11.1 Hz), 6.54 (1H, bs); MS(CI)m/z 435 (MH⁺).

EXAMPLE 95 Mutilin 14-[N-(1-methyl(6H)-6-oxopyridine-3-carbonyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-methyl (6H)-6-oxopyridine-3-carbonyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg, 1.50 mmol)was combined with I-methyl (6H)-6-oxopyridine-3-carbonyl chloride (600mg, 3.50 mmol) and silver cyanate (539 mg, 3.59 mmol) in drydichloromethane (30 ml) and the reaction stirred at room temperature for20 hours in subdued light and under an atmosphere of argon. The mixturewas filtered through Kieselguhr and the filtrate washed with saturatedaqueous sodium hydrogen carbonate (×2) and brine. After drying (MgSO₄)purification was accomplished by chromatography on silica gel elutingwith 80% ethyl acetate in hexane. The title compound was isolated as acolourless foam (559 mg, 73%); ν_(max) (CH₂ Cl₂) 3382, 2959, 1779, 1735,1704 and 1473 cm⁻¹ ; MS(CI) m/z 513 (MH⁺), 530 (MNH₄ ⁺).

Step 2. Mutilin-14-[N-(1-methyl(6H)-6-oxopyridine-3-carbonyl)]-carbamate

The product of Step 1 (550 mg, 1.07 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (5 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with ethyl acetate to yield thetitle compound (360 mg, 67%); ν_(max) (CH₂ Cl₂) 3427, 2935, 1778, 1734,1662 and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.78 (3H, d, J 6.6 Hz), 0.87 (3H,d, J 7.0 Hz), 1.08-1.83 (16H, m) including 1.18 (3H, s) and 1.48 (3H,s), 2.08-2.34 (4H, m), 3.36 (1H, dd, J 10.8, 6.6 Hz), 3.59 (3H, s), 5.22(1H, dd, J 17.3, 1.5 Hz), 5.38 (1H, dd, J 11.1, 1.5 Hz), 5.79 (1H, d, J8.5 Hz), 6.52 (1H, dd, J 17.3, 11.1 Hz), 6.54 (1H, d, J 9.5 Hz), 7.62(1H, dd, J 9.5, 2.6 Hz), 7.87 (1H, bs), 8.16 (1H, d, J 2.6 Hz); MS (EI)m/z 498 (M⁺). Found: 498.2741, C₂₈ H₃₈ N₂ O₆ requires 498.2730.

EXAMPLE 96 Mutilin 14-[N-(6-chloronicotinoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(6-chloronicotinoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (250 mg, 0.75 mmol)was combined with 6-chloronicotinoyl chloride (1.21 g, 7.0 mmol) andsilver cyanate (1.0 g, 6.67 mmol) in dry dichloromethane (15 ml) and thereaction stirred at room temperature for 10 minutes in subdued light andunder an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 20% ethylacetate in hexane. The title compound was isolated as a colourless foam(311 mg, 80%); ν_(max) (CH₂ Cl₂) 3413, 2930, 1780, 1719, 1697 and 1488cm⁻¹ ; MS(CI) m/z 517 (MH⁺), 534 (MNH₄ ⁺).

Step 2. Mutilin-14-[N-(6-chloronicotinoyl)]-carbamate

The product of Step 1 (300 mg, 0.58 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 50% ethyl acetate in hexane toyield the title compound (85 mg, 29%); ν_(max) (CH₂ Cl₂) 3413, 2939,1782, 1735, 1697, 1586 and 1489 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.78 (3H, d, J6.6 Hz), 0.89 (3H, d, J 7.0 Hz), 1.07-1.82 (16H, m) including 1.18 (3H,s) and 1.50 (3H, s), 2.08-2.33 (4H, m), 3.36 (1H, dd, J 10.7, 6.6 Hz),5.21 (1H, dd, J 17.3, 1.5 Hz), 5.33 (1H, dd, J 11.1, 1.5 Hz), 5.79 (1H,d, J 1 8.5 Hz), 6.49 (1H, dd, J 17.3, 11.1 Hz), 7.45 (1H, d, J 8.3 Hz),8.07 (1H, dd, J 8.3, 2.3 Hz), 8.08 (1H, bs), 8.74 (1H, d, J 2.3 Hz); 6Hz); MS (EI) m/z 512 (M⁺). Found: 512.2882, C₂₉ H₄₀ N₂ O₆ requires512.2886.

EXAMPLE 97 Mutilin 14-[N-(2-methoxyisonicotinoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2-methoxyisonicotinoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg, 1.50 mmol)was combined with 2-methoxyisonicotinoyl chloride (600 mg, 3.2 mmol) andsilver cyanate (500 mg, 3.30 mmol) in dry dichloromethane (20 ml) andthe reaction stirred at room temperature for 3 hours in subdued lightand under an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 30% ethylacetate in hexane. The title compound was isolated as a colourless foam(598 mg, 78%); ν_(max) (CH₂ Cl₂) 3410, 2931, 1781, 1720, 1698, 1559 and1473 cm⁻¹ ; MS(CI) m/z 517 (MH⁺), 534 (MNH₄ ⁺).

Step 2. Mutilin-14-[N-(2-methoxyisonicotinoyl)]-carbamate

The product of Step 1 (560 mg, 1.09 mmol) in dioxane (4 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (4 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 50% ethyl acetate in hexane toyield the title compound (374 mg, 69%); ν_(max) (CH₂ Cl₂) 3412,2946,1782, 1735, 1610, 1559 and 1474 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.78 (3H, d, J6.6 Hz), 0.89 (3H, d, J 7.0 Hz), 1.08-1.84 (16H, m) including 1.20 (3H,s) and 1.49 (3H, s), 2.10-2.37 (4H, m), 3.38 (1H, dd, J 10.6, 6.7 Hz),3.99 (3H, s), 5.24 (1H, dd, J 17.3, 1.5 Hz), 5.39 (1H, dd,J 11.1, 1.5Hz), 5.72 (1H, d, J 8.5 Hz), 6.53 (1H, dd, J 17.3, 11.1 Hz), 7.05 (1H,d, J 1.1 Hz), 7.18 (1H, dd, J 5.2, 1.1 Hz), 7.92 (1H, bs), 8.31 (1H, d,J 5.2 Hz); MS (EI) m/z 498 (M⁺). Found: 498.2726, C₂₈ H₂₉ N₂ O₆ requires498.2730.

EXAMPLE 98 Mutilin 14-[N-(morpholine-4-ylcarbonyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(morpholine-4-ylcarbonyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 g, 3.0 mmol)was combined with 4-morpholine carbonyl chloride (1.40 ml, 12.0 mmol)and silver cyanate (2.0 g, 13.3 mmol) in dry dichloromethane (45 ml) andthe reaction stirred at room temperature for 17 days in subdued lightand under an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 50% ethylacetate in hexane. The title compound was isolated as a colourless foam(990 mg, 67%); ν_(max) (CH₂ Cl₂) 3394, 2985, 1771, 1736, 1695 and 1421cm⁻¹ ; MS(CI) m/z 491 (MH⁺).

Step 2. Mutilin-14-[N-(morpholine-4-ylcarbonyl)]-carbamate

The product of Step 1 (500 mg, 1.02 mmol) in dioxane (5 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (5 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 70% ethyl acetate in hexane toyield the title compound (180 mg, 37%); ν_(max) (CH₂ Cl₂) 3391, 2928,1773, 1735, 1684, 1488 and 1458 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.78 (3H, d, J6.6 Hz), 0.85 (3H, d, J 7.0 Hz), 1.06-1.82 (16H, m) including 1.18 (3H,s) and 1.42 (3H, s), 2.04-2.38 (4H, m), 3.33 (1H, dd, J 10.4, 6.6 Hz),3.45 (4H, m), 3.70 (4H, m), 5.20 (1H, dd, J 17.3, 1.5 Hz), 5.32 (1H, dd,J 11.1, 1.5 Hz), 5.69 (1H, d, J 8.4 Hz), 6.51 (1H, dd, J 17.3, 11.1 Hz),6.68 (1H, bs); MS (CI) m/z 477 (MH⁺).

EXAMPLE 99 Mutilin 14-[N-(thiomorpholine-4-ylcarbonyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(thiomorpholine-4-ylcarbonyl)]-carbamate

A solution of (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (250mg, 0.75 mmol) in diethyl ether (5 ml) was added to a solution ofN-(chlorocarbonyl)-isocyanate (0.060 ml, 0.75 mmol) in diethyl ether (5ml) under an atmosphere of argon at -50° C. The temperature was raisedto 0° C. over 1.5 hours and then a solution of thiomorpholine (0.075 ml,0.75 mmol) and triethylamine (0.079 ml, 0.75 mmol) in diethyl ether (5ml) was added dropwise. The reaction mixture was stirred for 2 hours atroom temperature and then partitioned between 0.5M hydrochloric acid andethyl acetate. The organic layer was washed with brine. After drying(MgSO₄) purification was accomplished by chromatography on silica geleluting with 30% ethyl acetate in hexane. The title compound wasisolated as a colourless foam (144 mg, 38%); ν_(max) (CH₂ Cl₂) 3393,2928, 1771, 1739, 1682 and 1458 cm⁻¹ ; MS(Electrospray) m/z 505 [M-H]⁻.

Step 2. Mutilin-14-[N-(thiomorpholine-4-ylcarbonyl)]-carbamate

The product of Step 1 (170 mg, 0.34 mmol) in dioxane (1.5 ml) wastreated with a saturated solution of zinc chloride in conc. HCl (1.5 ml)and the reaction stirred at room temperature for 1 hour. The solutionwas poured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 50% ethyl acetate in hexane toyield the title compound (115 mg, 69%); ν_(max) (CH₂ Cl₂) 3393,2930,1772, 1736,1682,1458 and 1426 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.75 (3H, d, J 6.6Hz),0.89 (3H, d, J 7.0 Hz), 1.09-1.83 (16H, m) including 1.18 (3H, s)and 1.45 (3H, s), 2.04-2.35 (4H, m), 2.69 (4H, m), 3.34 (1H, dd, J 10.6,6.6 Hz), 3.73 (4H, m), 5.20 (1H, dd, J 17.3, 1.5 Hz), 5.33 (1H, dd, J1I1.1, 1.5 Hz), 5.69 (1H, d, J 8.7 Hz), 6.50 (1H, dd, J 17.3, 11.1 Hz),6.65 (1H, bs); MS (CI) m/z 493 (MH⁺).

EXAMPLE 100 Mutilin14-[N-(thiomorpholine-4-ylcarbonyl-1,1-dioxide)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(thiomorpholine-4-ylcarbonyl-11-dioxide)]-carbamate

A solution of (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(thiomorpholine-4-ylcarbonyl)]carbamate (120 mg, 0.24 mmol) inmethanol (2 ml) was cooled to 0° C. and treated with a solution of oxone(442 mg, 0.72 mmol) in water (2 ml). The reaction mixture was stirredfor 1 hour at room temperature and then partitioned between water anddichloromethane. The organic layer was washed with water and brine.After drying (MgSO₄) purification was accomplished by chromatography onsilica gel eluting with 50% ethyl acetate in hexane. The title compoundwas isolated as a colourless foam (73 mg, 57%); ν_(max) (CH₂ Cl₂) 3387,2931, 1775, 1742, 1694 and 1461 cm⁻¹ ; MS(CI) m/z 539 (MH⁺).

Step 2.Mutilin-14-[N-(thiomorpholine-4-ylcarbonyl-1I1-dioxide)]-carbamate

The product of Step 1 (220 mg, 0.40 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 80% ethyl acetate in hexane toyield the title compound (120 mg, 57%); ν_(max) (CH₂ Cl₂) 3388, 2938,1776, 1736, 1692, 1465 and 1426 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.72 (3H, d, J6.6 Hz), 0.90 (3H, d, J 7.0 Hz), 1.09-1.83 (16H, m) including 1.18 (3H,s) and 1.42 (3H, s), 2.07-2.34 (4H, m), 3.18 (4H, m), 3.37 (1H, dd, J10.6, 6.5 Hz), 3.92 (4H, m), 5.22 (1H, dd, J 17.3, 1.5 Hz), 5.33 (1H,dd, J 11.1, 1.5 Hz), 5.67 (1H, d, J 8.4 Hz), 6.46 (1H, dd, J 17.3, 11.1Hz), 6.80 (1H, bs); MS (CI) m/z 542 (MNH₄ ⁺).

EXAMPLE 101 Mutilin 14-[N-(1-methylpiperazin-4-ylcarbonyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-methylpiperazin-4-ylcarbonyl)]-carbamate

A solution of (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo4-epi-mutilin (500mg, 1.5 mmol) in diethyl ether (10 ml) was added to a solution ofN-(chlorocarbonyl)-isocyanate (0.12 ml, 1.5 mmol) in diethyl ether (10ml) under an atmosphere of argon at -50° C. The temperature was raisedto 0° C. over 1.5 hours and then a solution of 1-methylpiperazine (0.16ml, 1.5 mmol) and triethylamine (0.16 ml, 1.5 mmol) in diethyl ether (10ml) was added dropwise. The reaction mixture was stirred for 2 hours atroom temperature and then partitioned between 0.5M hydrochloric acid andethyl acetate. The organic layer was washed with brine. After drying(MgSO₄) purification was accomplished by chromatography on silica geleluting with 20% methanol in ethyl acetate. The title compound wasisolated as a colourless foam (170 mg, 23%); ν_(max) (CH₂ Cl₂) 3394,2942, 1769, 1740, 1684 and 1458 cm⁻¹ ; MS(CI) m/z 504 (MH⁺).

Step 2. Mutilin-14-[N-(1-methylpiperazin-4-ylcarbonyl)]-carbamate

The product of Step 1 (165 mg, 0.32 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 3 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 30% methanol in ethyl acetateto yield the title compound (81 mg, 52%); ν_(max) (CH₂ Cl₂) 3392, 2941,1771, 1736, 1683, 1488 and 1458 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.75 (3H, d, J6.6 Hz), 0.86 (3H, d, J 7.0 Hz), 1.00-1.80 (16H, m) including 1.12 (3H,s) and 1.38 (3H, s), 2.02-2.25 (4H, m), 2.30 (3H, s), 2.41 (4H, m), 3.35(1H, m), 3.45 (4H, m), 5.20 (1H, dd, J 17.3, 1.5 Hz), 5.35 (1H, dd, J11.1, 1.5 Hz), 5.70 (1H, d, J 8.4 Hz), 6.50 (1H, dd, J 17.3, 11.1 Hz),6.60 (1H, bs); MS (CI) m/z 490 (MH⁺).

EXAMPLE 102 Mutilin14-[N-(4-{4-(2-morpholinoethyloxy)}-benzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-acetoxybenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 mg, 3.0 mmol)was combined with 4-acetoxybenzoyl chloride (2.3 g, 11.0 mmol) andsilver cyanate (1.7 g, 11.3 mmol) in dry dichloromethane (30 ml) and thereaction stirred at room temperature for 3 hours in subdued light andunder an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 40% ethylacetate in hexane. The title compound was isolated as a colourless foam(1.5 g, 93%); ¹ H NMR (CDCl₃) 0.90 (3H, d, J 6.6Hz), 1.02 (3H, d, J 7.0Hz), 1.10-1.77 (12H, m) including 1.22 (3H, s) and 1.30 (3H, s),1.69-1.76 (2H, m), 1.95-2.05 (2H, m), 2.22 (1H, m), 2.32 (3H, s), 2.53(1H, dd, J 15.3, 10.1 Hz), 2.90 (1H, q, J 6.5 Hz), 3.20 (3H, s), 3.47(1H, m), 5.02 (1H, d, J 17.5 Hz), 5.30 (1H, d, J 10.7 Hz), 5.87 (1H, d,J 10.0 Hz), 6.72 (1H, dd, J 17.5, 10.7 Hz), 7.20 (2H, d, J 8.7 Hz), 7.88(2H,d, J 8.7 Hz), 7.95 (1H, bs).

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxybenzoyl)]-carbamate

The product of Step 1 (1.50 g, 2.78 mmol) in dioxane (20 ml) was treatedwith 1M aqueous sodium hydroxide solution (9 ml). The reaction mixturewas stirred at room temperature for 30 minutes under an atmosphere ofargon. The mixture was diluted with ethyl acetate and dilute aqueoushydrochloric acid, the layers separated, and the organic phase washedwith brine. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 50% ethyl acetate in hexane.The title compound was isolated as a colourless foam (1.30 g, 94%); ¹ HNMR (CDCl₃) 0.89 (3H, d, J 6.6 Hz), 1.00 (3H, d, J 7.0 Hz), 1.09-1.70(12H, m) including 1.20 (3H, s) and 1.30 (3H, s), 1.70-1.79 (2H, m),1.97-2.03 (2H, m), 2.20 (1H, m), 2.53 (1H, dd, J 15.3, 10.1 Hz), 2.92(1H, q, J 6.5 Hz), 3.23 (3H, s), 3.49 (1H, m), 5.01 (1H, d, J 17.5 Hz),5.29 (1H, d, J 10.7 Hz), 5.85 (1H, d, J 10.0 Hz), 6.12 (1H,exch), 6.70(1H, dd, J 17.5, 10.7 Hz), 6.94 (2H, d, J 8.7 Hz), 7.74 (2H,d, J 8.7Hz), 7.94 (1H, bs).

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-{4-(2-morpholinoethyloxy)}benzoyl)]-carbamate

The product of Step 2 (700 mg, 1.41 mmol) in acetone (14 ml) was treatedwith potassium carbonate (389 mg, 2.82 mmol) and4-(2-chloroethyl)morpholine hydrochloride (262 mg, 1.41 mmol). Thereaction mixture was heated to reflux for 16 hours under an atmosphereof argon. The mixture was diluted with ethyl acetate and water and thelayers separated. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 5% ethanol in ethyl acetate.The title compound was isolated as a colourless foam (275 mg, 32%);ν_(max) (CH₂ Cl₂) 3421, 2932, 1774, 1726, 1698, 1605 and 1474 cm⁻¹ ;MS(Electrospray) m/z 611 (MH⁺).

Step 4. Mutilin-14-[N-(4-{4-(2-morpholinoethyloxy)}benzoyl)]-carbamate

The product of Step 3 (265 mg, 0.43 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 1 hour. The solution was pouredinto ethyl acetate and saturated sodium hydrogen carbonate solution. Theaqueous phase was re-extracted with ethyl acetate and the combinedorganic phases were washed with saturated sodium chloride solution. Theorganic phase was dried (MgSO₄) and purified by chromatography on silicagel eluting with 70% ethyl acetate in hexane to yield the title compound(160 mg, 62%); ν_(max) (CH₂ Cl₂) 3418, 2939, 1775, 1732, 1605 and 1476cm⁻¹ ; ¹ H NMR (CDCl₃) 0.79 (3H, d, J 6.6 Hz), 0.86 (3H, d, J 7.0 Hz),1.10-1.82 (16H, m) including 1.15 (3H, s) and 1.49 (3H, s), 2.08-2.39(4H, m), 2.54 (4H, m), 2.80 (2H, t, J 5.7 Hz), 3.36 (1H, dd, J 10.8, 6.5Hz), 3.72 (4H, m), 4.13 (2H, t, J 5.7 Hz), 5.21 (1H, dd, J 17.3, 1.5Hz), 5.37 (1H, dd, J 11.1, 1.5 Hz), 5.82 (1H, d, J 8.4 Hz), 6.55 (1H,dd, J 17.3, 11.1 Hz), 6.92 (2H, d, J 8.9 Hz), 7.78 (2H, d, J 8.9 Hz),7.83 (1H, bs); MS(CI) m/z 597 (MH⁺).

EXAMPLE 103 Mutilin 14-[N-(3-(2-dimethylaminoethoxy)benzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-acetoxybenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 mg, 3.0 mmol)was combined with 3-acetoxybenzoyl chloride (1.8 g, 8.4 mmol) and silvercyanate (1.31 g, 8.7 mmol) in dry dichloromethane (30 ml) and thereaction stirred at room temperature for 2 hours in subdued light andunder an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 5% ethylacetate in dichloromethane to yield the title compound (960 mg, 59%);ν_(max) (CH₂ Cl₂) 3414, 2929, 1775, 1715, 1698 and 1475 cm⁻¹ ; MS (EI)m/z 539 (M⁺). Found: 539.2883, C₃₁ H₄₁ NO₇ requires 539.2883.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-hydroxybenzoyl)]-carbamate

The product of Step 1 (940 mg, 1.74 mmol) in dioxane (14 ml) was treatedwith 1M aqueous sodium hydroxide solution (5.6 ml). The reaction mixturewas stirred at room temperature for 30 minutes under an atmosphere ofargon. The mixture was diluted with ethyl acetate and dilute aqueoushydrochloric acid, the layers separated, and the organic phase washedwith brine. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 40% ethyl acetate in hexane toyield the title compound (629 mg, 73%); ν_(max) (CH₂ Cl₂) 3575, 3414,2929, 1776, 1713, 1697 and 1479 cm⁻¹ ; MS (CI) m/z 498 (MH⁺), 515 (MNH₄⁺).

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-(2-dimethylaminoethoxy)benzoyl)]-carbamate

The product of Step 2 (590 mg, 1.19 mmol) in acetone (10 ml) was treatedwith potassium carbonate (328 mg, 2.38 mmol) and 2-dimethylaminoethylchloride hydrochloride (171 mg, 1.19 mmol). The reaction mixture washeated to reflux for 16 hours under an atmosphere of argon. The mixturewas diluted with ethyl acetate and water and the layers separated. Afterdrying (MgSO₄) purification was accomplished by chromatography on silicagel eluting with 10% ethanol in ethyl acetate to yield the titlecompound (138 mg, 20%); ν_(max) (CH₂ Cl₂) 3419, 2943, 1776, 1713, 1698,1583 and 1477 cm⁻¹ ; MS (EI) m/z 568 (M⁺). Found: 568.3516, C₃₃ H₄₈ N₂O₆ requires 568.3512.

Step 4. Mutilin-14-[N-(3-(2-dimethylaminoethoxy)benzoyl)]-carbamate

The product of Step 3 (120 mg, 0.21 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 3% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (69 mg, 59%);ν_(max) (CH₂ Cl₂) 3412, 2961, 1778, 1732, 1706 and 1479 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.80 (3H, d, J 6.6 Hz), 0.89 (3H, d, J 7.0 Hz), 1.15-1.83 (16H,m) including 1.19 (3H, s) and 1.52 (3H, s), 2.03-2.28 (4H, m), 2.34 (6H,s), 2.74 (2H, t, J 5.6 Hz), 3.39 (1H, m), 4.10 (2H, t, J 5.6 Hz), 5.22(1H, dd, J 17.3, 1.5 Hz), 5.39 (1H, dd, J 11.1, 1.5 Hz), 5.83 (1H, d, J8.4 Hz), 6.56 (1H, dd, J 17.3, 11.1 Hz), 7.12 (1H, m), 7.28-7.40 (3H,m), 7.92 (1H, bs); MS (EI) m/z 554 (M⁺). Found: 554.3368, C₃₂ H₄₈ N₂ O₆requires 554.3356.

EXAMPLE 104 Mutilin 14-[N-(4-(3-dimethylaminopropyl)benzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-(3-dimethylaminopropyl)benzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxybenzoyl)]-carbamate (370 mg, 0.74 mmol) in acetone (10ml) was treated with potassium carbonate (207 mg, 1.50 mmol) and3-dimethylaminopropyl chloride hydrochloride (18 mg, 0.75 mmol). Thereaction mixture was heated to reflux for 16 hours under an atmosphereof argon. The mixture was diluted with ethyl acetate and water, and thelayers separated. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 5% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (170 mg, 39%);ν_(max) (CH₂ Cl₂) 3425, 2943, 1774, 1697, 1605 and 1468 cm⁻¹ ; MS (EI)m/z 582 (M⁺). Found: 582.3675, C₃₄ H₅₀ N₂ O₆ requires 582.3669.

Step 2. Mutilin-14-[N-(4-(3-dimethylaminopropyl)benzoyl)]-carbamate

The product of Step 1 (152 mg, 0.26 mmol) in dioxane (1 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (1 ml) and thereaction stirred at room temperature for 1.5 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 5% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (80 mg, 54%);ν_(max) (CH₂ Cl₂) 3418, 2956, 1775, 1732, 1605 and 1477 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.78 (3H, d, J 6.6 Hz), 0.87 (3H, d, J 7.0 Hz), 1.05-1.85 (16H,m) including 1.18 (3H, s) and 1.50 (3H, s), 1.95-2.30 (6H, m), 2.34 (6H,s), 2.55 (2H, t, J 7.1 Hz), 3.42 (1H, m), 4.08 (2H, t, J 6.3 Hz), 5.21(1H, dd, J 17.3, 1.5 Hz), 5.37 (1H, dd, J 11.1, 1.5 Hz), 5.82 (1H, d, J8.4 Hz), 6.56 (1H, dd, J 17.3, 11.1 Hz), 6.93 (2H, d, J 8.8 Hz), 7.74(2H, d, J 8.8 Hz), 7.85 (1H, bs); MS (EI) m/z 568 (M⁺). Found: 568.3499,C₃₃ H₄₈ N₂ O₆ requires 568.3512.

EXAMPLE 105 Mutilin14-[N-(4-[2-pyrrolidin-1-yl-ethoxy])-benzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-[2-pyrrolidin-1-yl-ethoxy]benzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxybenzoyl)]-carbamate (600 mg, 1.21 mmol) in acetone (10ml) was treated with potassium carbonate (333 mg, 2.41 mmol) and1-(2-chloroethyl)pyrrolidine hydrochloride (205 mg, 1.21 mmol). Thereaction mixture was heated to reflux for 16 hours under an atmosphereof argon. The mixture was diluted with ethyl acetate and water and thelayers separated. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 3% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (302 mg, 42%);ν_(max) (CH₂ Cl₂) 3053, 2985, 1774, 1697, 1605 and 1421 cm⁻¹ ; MS (CI)m/z 595 (MH⁺).

Step 2. Mutilin-14-[N-(4-[2-pyrrolidin-1-yl-ethoxy]benzoyl)]-carbamate

The product of Step 1 (280 mg, 0.47 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 4% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (52 mg, 19%);ν_(max) (CH₂ Cl₂) 3427, 1775, 1732, 1711, 1606 and 1478 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.79 (3H, d, J 6.6 Hz), 0.89 (3H, d, J 7.0 Hz), 1.10-1.85 (20H,m) including 1.18 (3H, s) and 1.52 (3H, s), 2.09-2.40 (4H, m), 2.62 (4H,m), 2.92 (2H, t, J 5.8 Hz), 3.46 (1H, m), 4.12 (2H, t, J 5.8 Hz), 5.22(1H, dd, J 17.3, 1.5 Hz), 5.38 (1H, dd, J 11.1, 1.5 Hz), 5.82 (1H, d, J8.4 Hz), 6.58 (1H, dd, J 17.3, 11.1 Hz), 6.97 (2H, d, J 8.8 Hz), 7.75(2H, d, J 8.8 Hz), 7.80 (1H, bs); MS (CI) m/z 581 (MH⁺).

EXAMPLE 106 Mutilin14-[N-(4-[3-(4-methylpiperazin-1-yl)-propyloxy]-benzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-[3-(4-methylpiperazin-1-yl)-propyloxy]benzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxybenzoyl)]-carbamate (600 mg, 1.21 mmol) in acetone (10ml) was treated with potassium carbonate (480 mg, 3.47 mmol) and1-(3-chloropropyl)-4-methylpiperazine dihydrochloride (302 mg, 1.21mmol). The reaction mixture was heated to reflux for 16 hours under anatmosphere of argon. The mixture was diluted with ethyl acetate andwater and the layers separated. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 5% (9:1methanol:ammonia (35%)) in dichloromethane to yield the title compound(230 mg, 30%); ν_(max) (CH₂ Cl₂) 3420, 2941, 1774, 1697, 1605 and 1467cm⁻¹ ; MS (EI) m/z 637 (M⁺). Found: 637.4085, C₃₇ H₅₅ N₃ O₆ requires637.4091.

Step 2.Mutilin-14-[N-(4-[3-(4-methylpiperazin-1-yl)-propyloxy]benzoyl)]-carbamate

The product of Step 1 (200 mg, 0.31 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 5% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (80 mg, 41%);ν_(max) (KBr) 3427, 2924, 1753, 1727, 1689, 1605 and 1465 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.80 (3H, d, J 6.6 Hz), 0.87 (3H, d, J 7.0 Hz), 1.14-2.52 (35H,m) including 1.18 (3H, s), 1.52 (3H, s) and 2.29 (3H, s), 3.36 (1H, m),4.08 (2H, t, J 6.3 Hz), 5.21 (1H, dd, J 17.3, 1.5 Hz), 5.38 (1H, dd, J11.1, 1.5 Hz), 5.82 (1H, d, J 8.4 Hz), 6.57 (1H, dd, J 17.3, 11.1 Hz),6.94 (2H, d, J 8.8 Hz), 7.73 (2H, d, J 8.8 Hz), 7.81 (1H, bs); MS (EI)m/z 623 (M⁺). Found: 623.3921, C₃₆ H₅₃ N₃ O₆ requires 623.3921.

EXAMPLE 107 Mutilin 14-[N-(3-fluoro-4-hydroxybenzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-acetoxy-3-fluorobenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 mg, 3.0 mmol)was combined with 4-acetoxy-3-fluorobenzoyl chloride (1.7 g, 7.5 mmol)and silver cyanate (1.20 g, 8.0 mmol) in dry dichloromethane (30 ml) andthe reaction stirred at room temperature for 2 hours in subdued lightand under an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 5% ethylacetate in dichloromethane to yield the title compound (1.61 g, 96%);ν_(max) (CH₂ Cl₂) 3413, 2930, 1777, 1716, 1697 and 1479 cm⁻¹ ; MS (CI)m/z 575 (MNH₄ ⁺).

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-fluoro-4-hydroxybenzoyl)]-carbamate

The product of Step 1 (1.59 g, 2.85 mmol) in dioxane (20 ml) was treatedwith 1M aqueous sodium hydroxide solution (9 ml). The reaction mixturewas stirred at room temperature for 30 minutes under an atmosphere ofargon. The mixture was diluted with ethyl acetate and dilute aqueoushydrochloric acid, the layers separated, and the organic phase washedwith brine. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 40% ethyl acetate in hexane toyield the title compound (1.42 g, 96%); ν_(max) (CH₂ Cl₂) 3547, 3417,2930, 1776, 1713, 1697, 1618 and 1479 cm⁻¹ ; MS (Electrospray) m/z 514[M-H]⁻.

Step 3. Mutilin-14-[N-(3-fluoro-4-hydroxybenzoyl)]-carbamate

The product of Step 2 (200 mg, 0.39 mmol) in dioxane (1 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 1.5 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 60% ethyl acetate in hexane toyield the title compound (110 mg, 56%); ν_(max) (KBr) 3307, 2931, 1731,1690, 1618, 1504 and 1457 cm⁻¹ ; ¹ H NMR (CDCl₃ +d₆ DMSO) 0.72 (3H, d, J6.6 Hz), 0.83 (3H, d, J 7.0 Hz), 1.05-1.76 (16H, m) including 1.10 (3H,s) and 1.42 (3H, s), 1.85-2.34 (5H, m), 3.39 (1H, dd, J 10.1, 6.6 Hz),5.13 (1H, dd, J 17.3, 1.5 Hz), 5.26 (1H, dd, J 11.1, 1.5 Hz), 5.72 (1H,d, J 8.4 Hz), 6.50 (1H, dd, J 17.3, 11.1 Hz), 6.92 (1H, m), 7.45 (1H,m), 7.58 (1H,m), 8.99 (1H, bs); MS (CI) m/z 519 (MNH₄ ⁺).

EXAMPLE 108 Mutilin14-[N-(4-[2-dimethylaminoethoxy]-3-fluorobenzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-[2-dimethylaminoethoxy]-3-fluorobenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-fluoro-4-hydroxybenzoyl)]-carbamate (613 mg, 1.19 mmol) inacetone (10 ml) was treated with potassium carbonate (328 mg, 2.38 mmol)and 2-dimethylaminoethyl chloride hydrochloride (171 mg, 1.19 mmol). Thereaction mixture was heated to reflux for 16 hours under an atmosphereof argon. The mixture was diluted with ethyl acetate and water and thelayers separated. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 2% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (360 mg, 52%);ν_(max) (CH₂ Cl₂) 3419, 2943, 1776, 1697, 1615 and 1497 cm⁻¹ ; MS (CI)m/z 587 (MH⁺).

Step 2.Mutilin-14-[N-(4-[dimethylaminoethoxy]-3-fluorobenzoyl)]-carbamate

The product of Step 1 (350 mg, 0.59 mmol) in dioxane (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 2 hours. The solution waspoured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 5% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (203 mg, 60%);ν_(max) (CH₂ Cl₂) 3414, 2944, 1777, 1732, 1713, 1615 and 1479cm⁻¹ ; ¹ HNMR (CDCl₃) 0.80 (3H, d, J 6.6 Hz), 0.89 (3H, d, J 7.0 Hz), 1.16-1.83(16H, m) including 1.18 (3H, s) and 1.49 (3H, s), 2.10-2.29 (4H, m),2.33 (6H, s), 2.79 (2H, t, J 5.7 Hz), 3.36 (1H, m), 4.17 (2H, t, J 5.7Hz), 5.21 (1H, dd, J 17.3, 1.5 Hz), 5.38 (1H, dd, J 11.1, 1.5 Hz), 5.82(1H, d, J 8.4 Hz), 6.54 (1H, dd, J 17.3, 11.1 Hz), 7.01 (1H, m),7.52-7.60 (2H, m), 7.82 (1H, bs); MS (CI) m/z 573 (MH⁺).

EXAMPLE 109 Mutilin14-[N-(4-[2-dimethylaminoethoxy]-3-methoxybenzoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-acetoxy-3-methoxybenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.0 mg, 3.0 mmol)was combined with 4-acetoxy-3-methoxybenzoyl chloride (820 mg, 4.75mmol) and silver cyanate (715 mg, 4.77 mmol) in dry dichloromethane (30ml) and the reaction stirred at room temperature for 2 hours in subduedlight and under an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 50% ethylacetate in dichloromethane to yield the title compound (1.37 g, 80%);ν_(max) (CH₂ Cl₂) 3417, 2931, 1775, 1713, 1698, 1604 and 1479 cm⁻¹ ; MS(EI) m/z 569 (M⁺). Found: 569.2991, C₃₂ H₄₃ NO₈ requires 569.2989.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxy-3-methoxybenzoyl)]-carbamate

The product of Step 1 (1.30 mg, 2.28 mmol) in dioxane (20 ml) wastreated with 1M aqueous sodium hydroxide solution (7.3 ml). The reactionmixture was stirred at room temperature for 2 hours under an atmosphereof argon. The mixture was diluted with ethyl acetate and dilute aqueoushydrochloric acid, the layers separated, and the organic phase washedwith brine. After drying (MgSO₄) purification was accomplished bychromatography on silica gel eluting with 20% ethyl acetate indichloromethane to yield the title compound (1.08 g, 90%); ν_(max) (CH₂Cl₂) 3519, 3424, 2930, 1773, 1697 and 1479 cm⁻¹ ; MS (EI) m/z 527 (M⁺).Found: 527.2889, C₃₀ H₄₁ NO₇ requires 527.2883.

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-4-[2-dimethylaminoethoxy]-3-methoxybenzoyl)]-carbamate

The product of Step 2 (1.04 g, 1.97 mmol) in acetone (20 ml) was treatedwith potassium carbonate (545 mg, 3.95 mmol) and 2-dimethylaminoethylchloride hydrochloride (284 mg, 1.97 mmol). The reaction mixture washeated to reflux for 16 hours under an atmosphere of argon. The mixturewas diluted with ethyl acetate and water and the layers separated. Afterdrying (MgSO₄) purification was accomplished by chromatography on silicagel eluting with 4% (9:1 methanol:ammonia (35%)) in dichloromethane toyield the title compound (185 mg, 16%); ν_(max) (CH₂ Cl₂) 3421, 2941,1773, 1697, 1599 and 1477 cm⁻¹ ; MS (CI) m/z 599 (MH⁺).

Step 4.Mutilin-14-[N-4-[2-dimethylaminoethoxy]-3-methoxybenzoyl)]-carbamate

The product of Step 3 (160 mg, 0.27 mmol) in dioxane (1.5 ml) wastreated with a saturated solution of zinc chloride in conc. HCl (1.5 ml)and the reaction stirred at room temperature for 2 hours. The solutionwas poured into ethyl acetate and saturated sodium hydrogen carbonatesolution. The aqueous phase was re-extracted with ethyl acetate and thecombined organic phases were washed with saturated sodium chloridesolution. The organic phase was dried (MgSO₄) and purified bychromatography on silica gel eluting with 4% (9:1 methanol:ammonia(35%)) in dichloromethane to yield the title compound (65 mg, 41%);ν_(max) (CH₂ Cl₂) 3418, 2962, 1776, 1732, 1600 and 1478 cm⁻¹ ; ¹ H NMR(CDCl₃) 0.80 (3H, d, J 6.6 Hz), 0.89 (3H, d, J 7.0 Hz), 1.12-1.90 (16H,m) including 1.19 (3H, s) and 1.52 (3H, s), 2.05-2.30 (4H, m), 2.35 (6H,s), 2.80 (2H, t, J 6.0 Hz), 3.39 (1H, m), 3.90 (3H, s), 4.12 (2H, t, J6.0 Hz), 5.23 (1H, dd, J 17.3, 1.5 Hz), 5.39 (1H, dd, J 11.1, 1.5 Hz),5.85 (1H, d, J 8.4 Hz), 6.58 (1H, dd, J 17.3, 11.1 Hz), 6.90 (1H, m),7.29-7.42 (2H, m), 7.85 (1H, bs); MS (EI) m/z 584 (M⁺). Found: 584.3474,C₃₃ H₄₈ N₂ O₇ requires 584.3474.

EXAMPLE 110 Mutilin14-{N-[(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylcarbonyl]}-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylcarbonyl]}-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (490 mg, 1.46 mmol)was combined with (3S,4R)-1-azabicyclo[2.2.1]hept-3-ylcarbonyl chloride(280 mg, 1.46 mmol) and silver cyanate (550 mg, 3.67 mmol) in drydichloromethane (20 ml). Triethylamine (0.20 ml, 1.46 mmol) was addedand the reaction stirred at room temperature for 16 hours in subduedlight and under an atmosphere of argon. The mixture was filtered throughKieselguhr and the filtrate washed with saturated aqueous sodiumhydrogen carbonate (×2) and brine. After drying (MgSO₄) purification wasaccomplished by chromatography on silica gel eluting with 4% (9:1methanol:ammonia (35%)) in dichloromethane to yield the title compound(276 mg, 38%); ν_(max) (CH₂ Cl₂) 3383, 2981, 1780, 1749, 1698, 1460 and1374 cm⁻¹ ; MS (EI) m/z 500 (M⁺). Found: 500.3248, C₂₉ H₄₄ N₂ O₅requires 500.3250.

Step 2. Mutilin-14{N-[(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylcarbonyl]}-carbamate

The product of Step 1 (260 mg, 0.52 mmol) in dioxane (3 ml) was treatedwith conc. HCl (3 ml) and the reaction stirred at room for 30 minutes.The solution was diluted with water and washed with dichloromethane(×2). The aqueous phase was basified with saturated aqueous sodiumhydrogen carbonate and the product extracted into dichloromethane. Theorganic phase was dried (MgSO₄) and concentrated to yield the titlecompound (187 mg, 74%); ν_(max) (CH₂ Cl₂) 3386, 2962, 1782, 1735, 1699and 1467 cm⁻¹ ; ¹ H NMR (d₆ -DMSO) 0.63 (3H, d, J 6.6 Hz), 0.81 (3H, d,J 7.0 Hz), 1.05-3.12 (29H, m) including 1.09 (3H, s) and 1.42 (3H, s),4.52 (1H, d, J 6.0 Hz, exch), 5.03-5.12 (2H, m), 5.51 (1H, d, J 7.8 Hz),6.21 (1H, dd, J 17.7, 11.1 Hz), 10 40 (1H, bs); MS(CI) m/z 487 (MH⁺).

EXAMPLE 111 Mutilin 14-(piperidin-4-oyl)-carbamate

Step 1. Mutilin11-dichloroacetyl-14-(1-tert-butoxycarbonylpiperidin-4-oyl)-carbamate

1-tert-Butoxycarbonylpiperidine-4-carboxylic acid [J. Med. Chem.,(1996), 39(10), 1943-5] (229 mg) was converted to the acid chloride withoxalyl chloride (152mg, 0.105 ml) and 1 drop of DMF in dichloromethane.Silver cyanate (300 mg) was added to the reaction mixture and themixture refluxed for 1 hr. After cooling mutilin 11-dichloroacetate (216mg) and tetrakis(triphenylphosphine)-palladium(0) (5 mg) was added andthe reaction mixture stirred at room temperature for 16 h. The mixturewas filtered through celite and the solvent removed from the filtrate invacuo. Following purification by silica gel chromatography the titlecompound was obtained as a colourless foam, (154 mg, 45%); ν_(max) (CH₂Cl₂) 3382, 1786, 1754, 1736, 1686 and 1473 cm⁻¹ ; MS(CI) m/z 702(M+NH₄)⁺.

Step 2. Mutilin 14-(1-tert-butoxycarbonylpiperidin-4-oyl)-carbamate

Mutilin11-dichloroacetate-14-(1-tert-butoxycarbonylpiperidin-4-oyl)-carbamate(150 mg) in tetrahydrofuran (1 ml) was treated with 1M aqueous sodiumhydroxide (1.5 ml) and vigorously stirred at room temperature for 1.5hr. The reaction mixture was diluted with ethyl acetate and washed with5% citric acid, brine, dried over anhydrous magnesium sulfate andconcentrated. After purification by silica gel chromatography, the titlecompound was obtained as a colourless solid, (47 mg, 37%); ν_(max) (CH₂Cl₂) 3385, 1784, 1735, 1699 and 1686 cm⁻¹ ; MS(CI) m/z 575 (M+H)⁺.

Step 3. Mutilin 14-(piperidin-4-oyl)-carbamate

Mutilin 14-(1-tert-butoxycarbonylpiperidin-4-oyl)-carbamate (45mg) indichloromethane at room temperature was treated with trifluoroaceticacid (90 mg, 0.06 ml) and the solution left 16 h. The solution wasconcentrated and dried in vacuo to a colourless solid, (36 mg, 97%);Crystallization from acetone/hexane afforded the title compound ascolourless prisms, m.p. 190-195° C.; ν_(max) (CH₂ Cl₂) 3382, 1780, 1735,1704 and 1677 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.73 (3H, d, J 6.6 Hz),0.90 (3H, d, J 6.8 Hz), 1.19 (3H, s), 1.43 (3H, s), 2.87 (2H, t, J 11.6Hz), 3.32 (3H, m), 5.23 (1H, d, J 18.6 Hz), 5.35 (1H, d, J 11.1 Hz),5.69 (1H, d, J 8.4 Hz), 6.48 (1H, dd, J 11.1, 18.6 Hz) and 7.90 (1H, vbrs); MS(CI) m/z 475 (M+H)⁺.

EXAMPLE 112 Mutilin14-(2,3-dihydroimidazol[2,1-b]thiazol-6-oyl)-carbamate

Step1. 2,3-Dihydroimidazol[1,2-b]thiazole-6-carboxylic acid

Ethyl 2,3-dihydroimidazol[1,2-b]thiazole-6-carboxylate, (Patent, WO94/10178, May 11, 1994) (760 mg) in ethanol (5 ml) was hydrolysed withaqueous sodium hydroxide at 60° C. for 3 hr. The solvent was removed invacuo and the residue re-dissolved in water and acidified to pH 3 with5M hydrochloric acid. No precipitate was formed. The aqueous solutionwas freeze-dried and the solid residue extracted with hot ethanol. Afterfiltration and removal of solvent the title compound was obtained as apale yellow amorphous solid, (621 mg, quant.); ¹ HNMR (CDCl₃) 3.93 (2H,t, J 7.0 Hz), 4.25 (2H, t, J 7.6 Hz) and 7.93 (1H, s).

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2,3-dihydroimidazol[2,1-b]thiazol-6-oyl)-carbamate

A suspension of 2,3-dihydroimidazol[1,2-b]thiazole-6-carboxylic acid(316 mg) in dry dichloromethane (3 ml) was treated with oxalyl chloride(381 mg, 0.26 ml) for 3 hr. The slurry that was formed was concentratedin vacuo to remove excess oxalyl chloride and the solid residuere-suspended in dry dichloromethane. The reaction mixture was cooled inan ice bath and triethylamine (202 mg, 0.28 ml) was slowly added. Thepale yellow solution/solid was warmed to room temperature and silvercyanate (600 mg) was added. The mixture was stirred at room temperature16 h. and (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (334 mg)added. The reaction mixture was stirred for 2 h. The mixture wasfiltered through celite. The filtrate was then washed with water,saturated aqueous sodium hydrogen carbonate dried over anhydrousmagnesium sulfate and concentrated. Purification by silica gelchromatography eluting with 80% and then 90% ethyl acetate/hexaneafforded the title compound as a colourless foam, (113 mg, 21%); ν_(max)(CH₂ Cl₂) 3374, 1769, 1728, 1698, 1543, 1945 and 1468 cm⁻¹ ; MS(CI) m/z530 (M+H)⁺.

Step 3. Mutilin 14-(2,3-dihydroimidazol[2,1-b]thiazol-6-oyl)-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2,3-dihydroimidazol[2,1-b]thiazol-6-oyl)-carbamate (214 mg) indioxan (1 ml) was treated at room temperature with Lukas reagent (1 ml).The reaction was exothermic and darkened. After 1 h, t.l.c. analysisshowed complete conversion to the product. The reaction mixture wasdiluted with ethyl acetate and neutralized with saturated aqueous sodiumhydrogen carbonate. The aqueous phase was extracted with ethyl acetateand the combined organic phases washed with brine, dried over anhydrousmagnesium sulfate and concentrated to a colourless solid. Triturationwith dichloromethane and filtering gave the title compound as a whiteamorphous solid, (97 mg, 47%); ν_(max) (KBr) 1762, 1732, 1637, 1543,1509 and 1464 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.63 (3H, d, J 6.0 Hz),0.81 (3H, d, J 6.7 Hz), 1.05 (3H, s), 1.39 (3H, s), 3.41 (1H, d, J 5.5Hz), 3.90 (2H, t, J 7.0 Hz) 4.24 (2H, t, J 7.0 Hz), 5.09 (2H, m), 5.53(7.8 Hz), 6.20 (1H, dd, J 11.2,17.6 Hz), 7.98 (1H, s) and 9.66 (1H, sexchangeable with D₂ O); MS(ES) m/z 516 (M+H)⁺.

EXAMPLE 113 Mutilin14-(2,3-dihydroimidazol[2,1-b]thiazol-5-oyl)-carbamate

Step1. 2,3-Dihydroimidazol[1,2-b]thiazole-5-carboxylic acid

Ethyl 2,3-dihydroimidazol[1,2-b]thiazole-5-carboxylate (formed as aside-product in the preparation of the thiazol-6-carboxylate, Example112) (3.84 g) was hydrolysed to the acid with aqueous sodium hydroxide(50 ml) as described in Example 112, Step 1. After acidification a whiteprecipitate was formed. This was filtered off, washed with water anddried overnight in vacuo. The title compound was obtained as a whitesolid, (2.86 g, 93%); ¹ HNMR (d6-DMSO) 3.96 (2H, t, J 7.3 Hz), 4.37 (2H,t, J 7.3 Hz), 7.51 (1H, s) and 12.89 (1H vbr s).

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2,3-dihydroimidazol[2,1-b]thiazol-5-oyl)-carbamate

2,3-dihydroimidazol[1,2-b]thiazole-5-carboxylic acid (316 mg) wasconverted to the acid chloride and coupled to(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin on the same scale,and using the same procedure described in Example 112, Step 2.Purification by silica gel chromatography using 50% and then 60% ethylacetate/hexane afforded the title compound as a colourless solid, (353,67%); ν_(max) (CH₂ Cl₂) 3419, 1769, 1723, 1697, 1520 and 1484 cm⁻¹ ;MS(EI) m/z 529 (M⁺).

Step 3. Mutilin 14-(2,3-dihydroimidazol[2,1-b]thiazol-5-oyl)-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2,3-dihydroimidazol[2,1-b]thiazol-5-oyl)-carbamate (324 mg) indioxan (2 ml) was treated with concentrated hydrochloric acid (1 ml) atroom temperature for 2 days. The reaction mixture was worked up asdescribed in Example 113, Step 3. The resultant colourless foamcrystallized on addition of dichloromethane. The title compound wasobtained as a colourless crystalline solid, (206 mg, 65%); ν_(max) (KBr)1735, 1712, 1527 and 1433 cm⁻¹ ; ¹ HNMR (d₆ -DMSO) inter alia 0.67 (3H,d, J 5.9 Hz), 0.83 (3H, d, J 6.8 Hz), 1.08 (3H, s) 1.45 (3H, s), 3.45(1H, t, J 5.5 Hz), 3.95 (2H, d, J 7.8 Hz), 4.54 (1H, d, J 6.0 Hz), 5.09(2H, m), 5.60 (1H, d, J 7.9 Hz), 7.87 (1H, s) and 10.5 (1H, s); MS(CI)m/z 515 (M⁺); Found: 515.2458, C₂₇ H₃₇ N₃ O₅ S requires 515.2452.

EXAMPLE 114 Mutilin 14-(1-Methylpiperidin-4-oyl)-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(1-methylpiperidin-4-oyl)-carbamate

1-Methylpiperidin-4-carboxylic acid (500 mg) was converted to thecorresponding acid chloride with thionyl chloride [J. Med. Chem.,(1990), 33(6), 1599]. A suspension of the acid chloride in drydichloromethane (5 ml) was treated with silver cyanate (1.04 g) and thereaction mixture refluxed for 1 h. After cooling,(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo4-epi-mutilin (334 mg) was addedfollowed by triethylamine (281 mg, 0.39 ml) after 10 m. The reactionmixture was filtered through celite, and the filtrate washed withsaturated aqueous sodium hydrogen carbonate. Following purification bysilica gel chromatography, the title compound was obtained as acolourless foam, (426 mg, 85%); ν_(max) (CH₂ Cl₂) 3381, 1781, 1749, 1698and 1474 cm⁻¹ ; MS(EI) m/z 502 (M⁺); Found: 502.3411, C₂₉ H₄₆ N₂ O₅requires 502.3407.

Step 2. Mutilin 14-(1-methylpiperidin-4-oyl)-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(1-methylpiperidin-4-oyl)-carbamate (1.08 g) in dioxan (8 ml), wastreated with concentrated hydrochloric acid (4 ml) at room temperaturefor 5 h. T.l.c. analysis showed complete conversion to the product. Thesolvents were removed in vacuo and the residual material dissolved inwater. The solution was extracted with dichloromethane. The aqueoussolution was basified with saturated aqueous sodium hydrogen carbonateto pH 8 and extracted with dichloromethane (three times). The combinedorganic phases were subsequently washed with brine, dried over anhydrousmagnesium sulfate and concentrated to give a colourless foam.Trituration with hexane afforded the title compound as a colourlessamporphous solid, (574 mg, 55%); ν_(max) (CH₂ Cl₂) 3385, 1782, 1736,1704 and 1474 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.73 (3H, d, J 6.7 Hz),0.89 (3H, d, J 7.0 Hz), 1.18 (3H, s), 1.42 (3H, s), 2.28 (3H, s), 3.36(1H, dd, J 6.7,10.2 Hz), 5.22 (1H, d, J 17.5 Hz), 5.36 (1H, d, J 11.0Hz), 5.70 (1H, d, J 8.4 Hz), 6.49 (1H, dd, J 11.0,17.3 Hz) and 7.43 (1H,s); MS(EI) m/z 488 (M⁺), Found: 488.3225, C₂₈ H₄₄ N₂ O₅ requires488.3250.

EXAMPLE 115 Mutilin 14-(1-Methylpiperidin-4-oyl)-carbamate Hydrochloridesalt

Mutilin 14-(1-methylpiperidin-4-oyl)-carbamate (350 mg) in ethyl acetate(5 ml) at room temperature was treated with a solution of 4M hydrogenchloride in dioxan in a dropwise fashion until no more precipitate wasformed. The white solid was removed by filtration, washed with ethylacetate and dried in vacuo. The title compound was obtained as anamporphous white solid, (30 mgs, 80%); ¹ HNMR (D₂ O) inter alia 0.69(3H, d, J 5.8 Hz), 0.92 (3H, d, J 6.8 Hz), 1.14 (3H, s), 1.38 (3H, s),2.89 (3H, s), 3.05 (2H, t, J 12.7 Hz), 5.19 (1H, d, J 17.5 Hz), 5.26(1H, d, J 11.1 Hz), 5.61 (1H, d, J 8.1 Hz) and 6.35 (1H, d, J 11.1,17.5Hz).

EXAMPLE 116 Mutilin 14-(2-Chloropropionyl)-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2Chloropropionyl)-carbamate

3-Chloropropionyl chloride (889 mg, 0.67 ml), silver cyanate (2.05 g)and (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (668 mg), indichloromethane (10 ml) were allowed to react at room temperature for 3days. The mixture was filtered through celite, washed with saturatedaqueous sodium hydrogen carbonate, dried over anhydrous magnesiumsulfate and concentrated, to give a gum. Purification by silica gelchromatography afforded the title compound as a crisp white foam, (909mg, 97%); ν_(max) (CH₂ Cl₂) 3382, 1785, 1752, 1711, 1699 and 1473 cm⁻¹ ;MS(CI) m/z 485 (M+NH₄)⁺.

Step 2. Mutilin 14-(2-Chloropropionyl)-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2-chloropropionyl)-carbamate (300 mg) in dioxan (2 ml), cooled to0-5° C. was treated with Lukas reagent (2 ml) and allowed to warm toroom temperature. After 2 h, the reaction mixture was diluted withdichloromethane and washed with water, saturated aqueous sodium hydrogencarbonate, brine and then dried over anhydrous magnesium sulfate. Afterpurification by silica gel chromatography, the title compound wasobtained as a colourless foam, (223 mg, 77%); ν_(max) (CH₂ Cl₂) 3624,3564, 3384, 1786, 1754, 1734, 1710 and 1473 cm⁻¹ ; ¹ HNMR (CDCl₃) interalia 0.74 (3H, d, J 6.8 Hz), 0.89 (3H, d, J 7.0 Hz), 1.19 (3H, s), 1.42(3H, s), 3.29 (2H, t, J 7.0 Hz), 3.37 (1H, dd, J 6.7,10.7 Hz), 3.80 (3H,t, 7.0 Hz), 5.24 (1H, d, J 17.4 Hz), 5.34 (1H, d, J 11.0 Hz), 5.70 (1H,d, J 8.5 Hz), 6.48 (1H, dd, J 11.0,17.4 Hz) and 7.50 (1H, s); MS(ES) m/z452 (M-H)⁻.

EXAMPLE 117 Mutilin 14-(2-diethylaminopropionyl)-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2-Diethylaminopropionyl)-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2-chloropropionyl)-carbamate (200 mg) in ethyl acetate (2 ml) atroom temperature was treated with diethylamine (312 mg, 0.44 ml). After2 h, no remaining starting material by t.l.c. analysis. The solution waswashed with saturated aqueous sodium hydrogen carbonate, water (twotimes), brine and then dried over anhydrous magnesium sulfate. Thesolution was concentrated to give the title compound as a colourlessfoam, (197 mg, 92%); ν_(max) (CH₂ Cl₂) 1770, 1697, 1520 and 1458 cm⁻¹ ;MS(EI) m/z 504 (M⁺), Found: 504.3548, C₂₉ H₄₈ N₂ O₅ requires 504.3563.

Step 2. Mutilin 14-(2-diethylaminopropionyl)-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(2-diethylaminopropionyl)-carbamate, (320 mg) was converted to thetitle compound as described in Example 116, Step 2. The product wasobtained as a colourless foam, (153 mg, 49%); ν_(max) (CH₂ Cl₂) 1772,1735, 1703 and 1520 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.76 (3H, d, J 6.6Hz), 0.87 (3H, d, J 7.0 Hz), 1.08 (6H, t, J 7.2 Hz), 1.17 (3H, s), 1.43(3H, s), 3.34 (1H, dd, J 6.5,11.2 Hz), 5.21 (1H, d, J 17.4 Hz), 5.37(1H, d, J 11.0 Hz), 5.71 (1H, d, J 8.5 Hz) and 6.59 (1H, dd, J 11.0,17.4Hz); MS(EI) m/z 490 (M⁺), Found: 490.3414, C₂₈ H₄₆ N₂ O₅ requires490.3407.

EXAMPLE 118 Mutilin 14-(Acryloyl)-carbamate

Step 1. Mutilin 14-(acryoyl)-carbamate

Mutilin 14-(2-chloropropionyl)-carbamate (150 mg) in dichloromethane (1ml) at room temperature was treated with triethylamine (67 mg, 0.092ml). After 2 h., t.l.c. analysis showed no starting material, Thesolution was purified by silica gel chromatography to give the titlecompound as a colourless foam, (135 mg, 98%); ν_(max) (CH₂ Cl₂) 3625,3563, 3389, 1779, 1735, 1697, 1625 and 1485 cm⁻¹ ; ¹ HNMR (CDCl₃) interalia 0.75 (3H, d, J 6.8 Hz), 0.89 (3H, d, J 7.0 Hz), 1.12 (3H, s), 1.45(3H, s), 3.37 (1H, dd, J 6.6,10.7 Hz), 5.23 (1H, d, J 17.3 Hz), 5.37(1H, d, J 11.1 Hz), 5.72 (1H, d, J 8.5 Hz), 5.89 (1H, d, J 10.4 Hz),6.50 (2H, dd, J 10.4,17.4 Hz), 7.06 (1H, dd, J 11.1,17.3 Hz) and 7.60(1H, s); MS(CI) m/z 435 (M+NH₄)⁺.

EXAMPLE 119 Mutilin 14-(1-Benzylpiperidin-4-oyl)-carbamate

Step 1. 1-Benzylpiperidine-4-carboxylic acid

Ethyl 1-benzylpiperidine-4-carboxylate (13.73 g) in methanol (100 ml)was treated with 40% aqueous sodium hydroxide (8.3 ml) at roomtemperature 16 h. The solvent was removed in vacuo and the residuere-dissolved in water (100 ml), acidified with dilute hydrochloric acidto pH 4 and concentrated. The residue was extracted with hot ethanol(200 ml), filtered and concentrated again. Addition of dichloromethaneresulted in crystallization giving the title compound as a colourlesscrystaline solid, (3.24 g, 27%). Removal of solvent from the filtrateand trituration with ether gave a second batch as an amorphous whitesolid, (9.24 g, 73%); ν_(max) (CH₂ Cl₂) 2496 (vbr), 1720 and 1604 (br)cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(1-Benzylpiperidin-4-oyl)-carbamate

1-Benzylpiperidine-4-carboxylic acid (500 mg) in dichloromethane (5 ml)was converted to the acid chloride with oxalyl chloride (319 mg, 0.22ml) and 1 drop of DMF over 1 h. To this homogeneous solution was addedsilver cyanate (684 mg) and the reaction mixture refluxed for 1 h. Themixture was cooled to room temperature and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (334 mg) added.After 5 m, triethylamine (0.32 ml) was added dropwise. After 2 h. thereaction mixture was filtered through celite, washed with water,saturated aqueous sodium hydrogen carbonate, brine and dried overanhydrous magnesium sulfate. Removal of solvent in vacuo, andpurification of the residue by silica gel chromatography, afforded thetitle compound as a colourless foam, (355 mg, 61%); ν_(max) (CH₂ Cl₂)3384, 1782, 1784, 1699 and 1478 cm ⁻¹ ; MS(ES) m/z 579 (M+H)⁺.

Step 3. Mutilin 14-(1-Benzylpiperidin-4-oyl)-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(1-benzylpiperidin-4-oyl)-carbamate (304 mg) in dioxan (0.5 ml) wastreated with concentrated hydrochloric acid (0.5 ml) until t.l.c.analysis showed no starting material. The solvents were removed undervacuum and the residue partitioned between saturated aqueous sodiumhydrogen carbonate and dichloromethane. The organic phase was dried overanhydrous magnesium sulfate and the solvent removed in vacuo. The crudeproduct was purified by silica gel chromatography to give the titlecompound as a foam, (172 mg, 58%); ν_(max) (CH₂ Cl₂) 3622, 3562, 3383,1782, 1735, 1703 and 1477 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.72 (3H, d,J 6.6 Hz), 0.88 (3H, d, J 7.0 Hz), 1.18 (3H, s), 1.42 (3H, s), 3.36 (1H,dd, J 6.6,10.5 Hz), 3.51 (2H, s), 5.21 (1H, d, J 17.3 Hz), 5.35 (1H, d,J 10.9 Hz), 5.69 (1H, d, J 8.4 Hz), 6.48 (1H, d, J 10.9,17.3 Hz) and7.30 (4H, m); MS(CI) m/z 564 (M⁺), Found: 564.3538, C₃₄ H₄₈ N₂ O₅requires 564.3564.

EXAMPLE 120 Mutilin 14-[1-(4-Methoxybenzyl)piperidin-4-oyl]-carbamate

Step 1. Ethyl 1-(4-methoxybenzyl)piperidine-4-carboxylate

Ethyl isonipecotate (5 g, 4.9 ml) and 4-methoxybenzyl chloride (5 g,4.44 ml) in DMF (40 ml) with potassium carbonate (8.8 g) was heated to70° C. for 2 h, then room temperature for 2 days, and again at 70° C.for 2 h. The reaction mixture was partitioned between ethylacetate/water. The organic layer was washed with water (2×), brine,dried over anhydrous magnesium sulfate and concentrated. The titlecompound was obtained as a yellow oil, (8.05 g, quant.); ν_(max) (CH₂Cl₂) 1725, 1611, 1585, 1511 and 1466 cm⁻¹ ; MS(EI) m/z 277 (M⁺), Found:277.1682, C₁₆ H₂₃ NO₃ requires 277.1678.

Step 2. 1-(4-methoxybenzyl)piperidine-4-carboxylic acid

Ethyl 1-(4-methoxybenzyl)piperidine-4-carboxylate, (8.05 g) washydrolysed to the corresponding acid with sodium hydroxide as describedin Example 119, Step 1. Following isolation of the crude product, thefoam was triturated with ether overnight to give the title compound as awhite, crystalline solid, (6.23 g, 86%); ν_(max) (KBr) 1731, 1613, 1516and1457 cm⁻¹ ; MS(EI) m/z 249 (M⁺), Found 249.1368, C₁₄ H₁₉ NO₃ requires249.1365.

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[1-(4-methoxybenzyl)piperidin-4-oyl]-carbamate

1-(4-Methoxybenzyl)piperidine-4-carboxylic acid (747 mg) was convertedto the acid chloride with oxalyl chloride (0.27 ml) in dichloromethane(10 ml) and then reacted with silver cyanate (600 mg) and coupled to(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg) in thepresence of triethylamine (0.42 ml) as described in example 119, Step 2.After purification the title compound was obtained as a colourless foam,(515 mg, 56%); ν_(max) (CH₂ Cl₂) 3383, 1782, 1749, 1699, 1611, 1511 and1468 cm⁻¹ ; MS(EI) m/z 608 (M⁺), Found: 608.3813, C₃₆ H₅₂ N₂ O₆ requires608.3825.

Step 4. Mutilin 14-[1-(4-Methoxybenzyl)piperidin-4-oyl]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[1-(4-methoxybenzyl)piperidin-4-oyl]-carbamate (485 mg) in dioxan (2ml) was converted to the title compound as described in Example 119,Step 3. After purification the product was obtained as a colourlessfoam, (433 mg, 92%); ν_(max) (CH₂ Cl₂) 3624, 3565, 3385, 1783, 1734,1705, 1611, 1511 and 1468 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.73 (3H, d,J 6.7 Hz), 0.89 (3H, d, J 6.9 Hz), 1.18 (3H, s), 1.43 (3H, s), 2.61 (2H,s), 3.81 (3H, s), 5.22 (1H, d, J 19.4 Hz), 5.36 (1H, d, J 11.1 Hz), 5.70(1H, d, J 8.0 Hz), 6.49 (1H, dd, J 11.1,19.4 Hz), 6.85 (2H, d, J 8.6Hz), 7.22 (2H, d, J 8.6 Hz) and 7.32 (1H, s); MS(EI) m/z 594 (M⁺),Found: 594.3657, C₃₅ H₅₀ N₂ O₆ requires 594.3669.

EXAMPLE 121 Mutilin 14-[1-(4-Methoxybenzyl)piperidin-4-oyl]-carbamateHydrochloride salt

Mutilin 14-[1-(4-methoxybenzyl)piperidin-4-oyl]-carbamate (100 mg) inethyl acetate (1 ml) was treated with 4M hydrogen chloride in dioxan,dropwise until no further precipitation was observed. The white solidwas filtered off, washed with ethyl acetate and dried under vacuum. Thetitle compound was obtained as an amorphous white solid, (70 mg, 66%); ¹HNMR (d₆ -DMSO) inter alia 0.63 (3H, d, J 6.2 Hz), 0.83 (3H, d, J 6.7Hz), 1.08 (3H, s), 1.40 (3H, s), 3.79 (3H, s), 4.20 (2H, br s), 4.56(1H, d, J 5.9 Hz), 5.06 (1H, d, J 11.1 Hz), 5.10 (1H, d, J 17.6 Hz),5.50 (1H, d, J 7.8 Hz), 6.22 (1H, dd, J 11.0,17.6 Hz), 7.01 (2H, d, J8.5 Hz), 7.50 (2H, d, J 8.5 Hz), 10.30 (1H, br s) and 10.51 (1H, s).

EXAMPLE 122 Mutilin 14-[1-(4-Fluorobenzyl)piperidin-4-oyl]-carbamate

Step 1. Ethyl 1-(4-Fluorobenzyl)piperidine-4-carboxylate

Ethyl isonipecotate (5 g, 4.9 ml) was alkylated with 4-fluorobenzylbromide, (6.02 g, 3.97 ml) in DMF (40 ml) in the presence of potassiumcarbonate (8.8 g) as described in Example 120, Step 1. The titlecompound was obtained as a yellow oil, (7.52 g, 89%); ν_(max) (CH₂ Cl₂)1725, 1603, 1508 and 1449 cm⁻¹ ; MS(EI) m/z 265 (M⁺), Found: 265.1478,C₁₅ H₂₀ FNO₂ requires 265.1478.

Step 2. 1-(4-Fluorobenzyl)piperidine-4-carboxylic acid

Ethyl 1-(4-fluorobenzyl)piperidine-4-carboxylate (7.52 g) was hydrolysedwith 40% sodium hydroxide (4.3 ml) as described in Example 120, Step 2.After work-up the title compound was obtained as a colourless solid,(4.26 g, 63%); ν_(max) (KBr) 1722, 1605, 1511 and 1447 cm⁻¹ ; MS(EI) m/z237 (M⁺), Found: 237.1160, C₁₃ H₁₆ FNO₂ requires 237.1165.

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[1-(4-Fluorobenzyl)piperidin-4-oyl]-carbamate

1-(4-Fluorobenzyl)piperidine-4-carboxylic acid (711 mg) was converted tothe acid chloride with oxalyl chloride (0.27 ml), treated with silvercyanate (600 mg) and coupled to(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg) in thepresence of triethylamine (0.42 ml) as described in Example 120, Step 3.Following purification the title compound was isolated as a colourlessfoam, (539 mg, 60%); ν_(max) (CH₂ Cl₂) 3678, 3381, 1781, 1748, 1699,1603, 1508 and 1478 cm⁻¹ ; MS(ES) m/z 597 (MH)⁺.

Step 4. Mutilin 14-[1-(4-Fluorobenzyl)piperidin-4-oyl]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[1-(4-fluorobenzyl)piperidin-4-oyl]-carbamate (510 mg) was convertedto the title compound as described in Example 120, Step 4. Afterpurification the product was obtained as a colourless foam, (346 mg,70%); ν_(max) (CH₂ Cl₂) 3563, 3386, 1783, 1735, 1705, 1604, 1508 and1478 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.72 (3H, d, J 6.6 Hz), 0.89 (3H,d, J 8.0 Hz), 1.19 (3H, s), 1.43 (3H, s), 3.37 (1H, dd, J 6.6,10.2 Hz),3.45 (2H, s), 5.22 (1H, d, J 17.5 Hz), 5.36 (1H, d, J 9.9 Hz), 5.70 (1H,d, J 8.4 Hz), 6.49 (1H, dd, J 9.9,17.5 Hz), 7.00 (2H, m), 7.26 (2H, m)and 7.35 (1H, s); MS(EI) m/z 582 (M⁺), Found: 582.3472, C₃₅ H₄₇ FN₂ O₅requires 582.3469.

EXAMPLE 123 Mutilin 14-[1-(pyridin-2-ylmethyl)piperidin-4-oyl]-carbamate

Step 1. Ethyl 1-(pyridin-2-ylmethyl)piperidine-4-carboxylate

Ethyl isonipecotate (4.79 g, 4.7 ml) was alkylated with2-chloromethylpyridine hydrochloride (5 g) and potassium carbonate(12.62 g) in DMF (40 ml) as described in Example 120, Step 1. The titlecompound was obtained as a yellow oil, (6,09 g, 81%); ν_(max) (CH₂ Cl₂)1724, 1590, 1570, 1476, 1449 and 1433 cm⁻¹ ; MS(ES) m/z 249 (MH)⁺.

Step 2. 1-(pyridin-2-ylmethyl)piperidine-4-carboxylic acid

Ethyl 1-(pyridin-2-ylmethyl)piperidine-4-carboxylate (6.08 g) washydrolysed with 40% sodium hydroxide (3.7 ml) in methanol (50 ml) asdescribed in Example 120, Step 2. After isolation the title compound wasobtained as a pale green foam, (5.01 g, 93%). A portion of the materialwas shown to crystallize from dichloromethane to give a colourlesscrystalline solid; ν_(max) (KBr) 1685 (br), 1601 and 1463 cm⁻¹ ; MS(ES)m/z 221 (MH)⁺.

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[1-(pyridin-2-ylmethyl)piperidin-4-oyl]-carbamate

1-(Pyridin-2-ylmethyl)piperidine-4-carboxylic acid (440 mg) wasconverted to the acid chloride with oxalyl chloride (267 mg, 0.18 ml)and treated with silver cyanate (450 mg) and then coupled to(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (334 mg) in thepresence of triethylamine (0.28 ml), as described in Example 120, Step3. After purification the title compound was isolated as a pale yellowfoam, (267 mg, 46%); ν_(max) (CH₂ Cl₂) 3382, 1782, 1749, 1699, 1590 and1475 cm⁻¹ ; MS(EI) m/z 580 (MH)⁺, Found: 580.3741, C₃₄ H₅₀ N₃ O₅requires 580.3750.

Step 4. Mutilin 14-[1-(pyridin-2-ylmethyl)piperidin-4-oyl]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[1-(pyridin-2-ylmethyl)piperidin-4-oyl]-carbamate (248 mg) wasconverted with concentrated hydrochloric acid as described in Example120, Step 4. After work-up, the crude product was re-dissolved in dilutehydrochloric acid washed with dichloromethane, basified with saturatedaqueous sodium hydrogen carbonate and re-extracted. After drying andremoval of solvent the title compound was obtained as a pale yellowsolid, (135 mg, 56%); ν_(max) (CH₂ Cl₂) 3676, 3622, 3564, 3384, 1782,1735, 1703, 1590 and 1475 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.73 (3H, d,J 6.6 Hz), 0.89 (3H, d, J 6.9 Hz), 1.18 (3H, s), 1.42 (3H, s), 3.36 (1H,dd, J 6.6,10.5 Hz), 3.67 (3H, s), 5.22 (1H, d, J 17.3 Hz), 5.36 (1H, d,J 11.1 Hz), 5.70 (1H, d, J 8.4 Hz), 6.49 (1H, dd, J 11.1,17.3 Hz), 7.17(1H, m), 7.45 (2H, m), 7.66 (1H, m) and 8.55 (1H, d, J 4.0 Hz); MS (ES)m/z 565 (M⁺); Found 565.3527, C₃₃ H₄₇ N₃ O₅ requires 565.3516.

EXAMPLE 124 Mutilin14-{1-[(2-methylthiazol-4-yl)methyl]-piperidin-4-oyl}-carbamate

Step 1. Ethyl 1-[(2-methylthiazol-4-yl)methyl]piperidine-4-carboxylate

Ethyl isonipecotate (3.14 g, 3.08 ml) was alkylated with4-chloromethyl-2-methylthiazole hydrochloride (3.68 g) in DMF (40 ml)with potassium carbonate (8.28 g) as previously described in Example120, Step 1. After purification by silica gel chromatography the titlecompound was isolated as a yellow oil, (3.26 g, 61%); ν_(max) (CH₂ Cl₂)1724 cm⁻¹ ; MS(EI) m/z 269 (MH)⁺, Found: 269.1318, C₁₃ H₂₁ N₂ O₂ Srequires 269.1324.

Step 2. 1-[(2-methylthiazol-4-yl)methyl]piperidine-4-carboxylic acid

Ethyl 1-[(2-methylthiazol-4-yl)methyl]piperidine-4-carboxylate (3.06 g)was hydrolysed to the acid with 40% sodium hydroxide (1.73 ml) asdescribed in Example 120, Step 2. After purification the title compoundwas isolated as a colourless solid, (3.08 g, 99%); ν_(max) (KBr) 1719,1665, 1591 and 1392 cm⁻¹ ; MS(EI) m/z 240 (M⁺), Found: 240.0934, C₁₁ H₁₆N₂ O₂ S requires 240.0932.

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{1-[(2-methylthiazol-4-yl)methyl]piperidin-4-oyl}-carbamate

1-[(2-Methylthiazol-4-yl)methyl]piperidine-4-carboxylic acid (720 mg)was converted to the acid chloride with oxalyl chloride (0.27 ml),treated with silver cyanate (600 mg) and coupled to(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (500 mg) in thepresence of triethylamine (0.42 ml), as previously outlined in Example120, Step 3. Following purification the title compound was obtained as apale yellow foam, (405 mg, 45%); ν_(max) (CH₂ Cl₂) 3382, 1781, 1784,1698 and 1478 cm⁻¹ ; MS (EI) m/z 599 (M⁺); Found 599.3406, C₃₃ H₄₉ N₃ O₅S requires 599.3392.

Step 4. Mutilin14-{1-[(2-methylthiazol-4-yl)methyl]piperidin-4-oyl}-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{1-[(2-methylthiazol-4-yl)methyl]piperidin-4-oyl}-carbamate (391 mg)was converted to the title compound as described in Example 121, Step 4.The product was obtained as a white solid, (241 mg, 63%); ν_(max) (CH₂Cl₂) 3677, 3384, 1783, 1735, 1705 and 1477 cm⁻¹ ; ¹ HNMR (CDCl₃) interalia 0.73 (3H, d, J 6.6 Hz), 0.89 (3H, d, J 6.9 Hz), 1.18 (3H, s), 1.42(3H, s), 2.71 (3H, s), 2.99 (2H, d, J 10.3 Hz), 3.36 (1H, dd, J 6.6,10.5Hz), 3.63 (2H, s), 5.24 (1H, d, J 17.0 Hz), 5.36 (1H, d, J 11.1 Hz),5.72 (1H, d, J 8.4 Hz), 6.48 (1H, dd, J 11.1,17.0 Hz), 6.95 (1H, s) and7.38 (1H, s).

EXAMPLE 125 Mutilin 14-(N-3-pyridylacetyl)-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-3-pyridylacetyl)-carbamate

3-Pyridylacetic acid (520 mg, 3 mmol) in dichloromethane (5 ml) wastreated with oxalyl chloride (0.45 ml, 5.2 mmol) and one drop of DMF atroom temperature for 2 h. The solvent and excess oxalyl chloride wereremoved in vacuo. The residue was dissolved in toluene and the solventagain removed in vacuo.

The crude acid chloride in dry dichloromethane (10 ml) was treated withsilver cyanate (900 mg, 6 mmol) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1 mmol).After stirring at room temperature for 18 h the title compound wasisolated by the procedure described in Example 31, Step 2, (360 mg,72%); ν_(max) (CH₂ Cl₂) 3380, 1752 and 1699 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.80(3H, d, J6.9 Hz), 1.01 (3H, d, J6.4 Hz), 1.08-1.37 (3H, m), 1.19 (3H,s), 1.21 (3H, s), 1.56 (4H, m), 1.73 (1H, d, J11.3 Hz), 1.99 (2H, m),2.20 (1H, m), 2.49 (1H, dd, J15.2, 10.1 Hz), 2.88 (1H, q, J6.3 Hz), 3.21(3H, s), 3.44 (1H, m), 4.18 (2H, m), 5.04 (1H, d, J17.5 Hz), 5.34 (1H,d, J10.8 Hz), 5.74 (1H, d, J9.9 Hz), 6.62 (1H, dd, J17.5, 10.6 Hz), 7.28(2H, m), 7.65 (1H, dt, J 7.8, 1.9 Hz) 7.72 (1H, s), 8.54 (1H, s); MS(NH₃ DCI) m/z 497 (MH⁺), Found: 496.2948, C₂₉ H₄₀ N₂ O₅ requires496.2937.

Step 2. Mutilin 14-(N-3-pyridylacetyl)-carbamate

The product from step 1, (310 mg) in dioxan (2 ml) was treated with asaturated solution of zinc chloride in conc. HCl (2 ml), as for Example1 Step 2, to afford the title compound, (173 mg, 58%); ν_(max) (CH₂ Cl₂)3383, 1754, 1734, 1716 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.70 (3H, d, J6.7 Hz),0.91 (3H, d, J7.0 Hz), 1.17 (1H, m), 1.19 (3H, s), 1.40 (3H, s),1.36-1.82 (8H, m), 2.05-2.36 (5H, m), 3.37 (1H, dd, J10.1, 6.7 Hz), 4.14(2H, AB quartet, J 16.3 Hz), 5.24 (1H, dd, J17.4, 1.4 Hz), 5.39 (1H, dd,J11.1, 1.3 Hz), 5.71 (1H, d, J8.4 Hz), 6.49 (1H, dd, J17.4, 11.0 Hz),7.26 (1H, m), 7.56 (1H, s), 7.63 (1H, d, J7.8 Hz), 8.52 (2H, m); MS (NH₄DCI) m/z 483 (MH⁺), Found: 483.2856, C₂₈ H₃₈ N₂ O₅ requires 483.2859.

EXAMPLE 126 Mutilin 14-(N-2-pyridylmethyl)-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-(N-2-pyridylmethyl)-carbamate

2-Aminomethylpyridine (0.31 ml, 3 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin-14-chloroformate(400 mg, 1 mmol) in dichloromethane (10 ml), as for Example 12 Step 2,to afford the title compound (463mg, 98%); ν_(max) (CH₂ Cl₂) 3446, 1709cm⁻¹ ; ¹ H NMR (CDCl₃) 0.85 (3H, d, J6.9 Hz), 0.98 (3H, d, J6.5 Hz),1.05-1.61 (6H, m), 1.19 (3H, s), 1.22 (3H, s), 1.68 (1H, d, J15.3 Hz),1.71 (1H, d, J11.2 Hz), 1.99 (2H, m), 2.19 (1H, m), 2.43 (1H, dd, J15.1,10.1 Hz), 2.94 (1H, q, J6.4 Hz), 3.22 (3H, s), 3.46 (1H, ddd, J11.3,8.2, 5.3 Hz), 4.52 (2H, t, J5.3 Hz), 5.00 (1H, d, J17.5 Hz), 5.29 (1H,d, J10.7 Hz), 5.68 (2H, m), 6.77 (1H, dd, J17.5, 10.6 Hz), 7.20 (1H, dd,J7.5, 5.3 Hz), 7.29 (1H, m) 7.67 (1H, s), 8.55 (1H, d, J4.5 Hz); MS (EI)m/z 468 (M⁺), (NH₃ DCI) m/z 469 (MH⁺), Found: 468.2991, C₂₈ H₄₀ N₂ O₄requires 468.2988.

Step 2. Mutilin 14-(N-2-pyridylmethyl)-carbamate

The product from step 1, (398 mg) in dioxan (2 ml) was treated with asaturated solution of zinc chloride in conc. HCl (2 ml), as for Example1 Step 2, to afford the title compound, (184 mg, 48%); ν_(max) (CH₂ Cl₂)3445, 1732, 1713 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.75 (3H, d, J6.0 Hz), 0.86 (3H,d, J7.0 Hz), 1.1 (1H, m), 1.17 (3H, s), 1.42 (3H, s), 1.43 (4H, m), 1.71(4H, m), 2.04 (2H, m), 2.21 (2H, m), 2.37 (1H, quintet, J6.8 Hz), 3.35(1H, dd, J10.8, 6.7 Hz), 4.48 (2H, m), 5.20 (1H, dd, J17.4, 1.5 Hz),5.34 (1H, d, J11.1 Hz), 5.68 (2H, includes 1H d, J8.4 Hz), 6.59 (1H, dd,J17.4, 11.0 Hz), 7.20 (2H, m), 7.62 (1H, td, J7.6, 1.7 Hz), 8.53 (1H, d,J4.3 Hz); MS (EI) m/z 455 (MH⁺), (NH₃ DCI) m/z 455 (MH⁺), Found:454.2833, C₂₇ H₃₈ N₂ O₄ requires 454.2832.

EXAMPLE 127 (E)-Mutilin14-[N-3-(1-methyl-1,2,3-triazol-4-yl)acryloyl]-carbamate

Step 1: Methyl-(E)-3-(1-methyl-1,2,3-triazol-4-yl)acrylate

1-Methyl-1,2,3-triazol-4-carboxaldehyde (1 g, 9 mmol) was added to asolution of methoxycarbonylmethylene triphenylphosphorane (4.5 g, 13.5mmol) in dichloromethane (50 ml) and stirred at room temperature for 3.5hours. The solvent was removed and the residue purified by silica gelchromatography to afford the title compound, (3.2 g).

Step 2: (E)-3-(1-Methyl-1,2,3-triazol-4-yl)acrylic acid

10% Sodium hydroxide solution (3 ml) was added to a solution of theproduct from step 1 (3.2 g). The mixture was stirred at room temperaturefor 15 hours, further 10% sodium hydroxide solution (2 ml) added andthen heated to reflux for 3 hours. On cooling the reaction mixture waspartitioned between ethyl acetate and water. The organics werere-extracted with saturated sodium hydrogen carbonate solution and thecombined aqueous extracts acidified to pH 1 with conc. hydrochloricacid. After extraction into ethyl acetate and dying over magnesiumsulphate the solvent was removed to afford the title compound, (748 mg);¹ H NMR (d⁶ -DMSO) 4.07 (3H, s), 6.53 (1H, d, J16.0 Hz), 7.53 (1H, d,J16.0 Hz), 8.44 (1H, s), 12.48 (1H, br).

Step 3: (E)-(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-3-(1-methyl-1,2,3-triazol-4-yl)acryloyl]-carbamate

(E)-3-(1-Methyl-1,2,3-triazol-4-yl)acrylic acid (306 mg, 2 mmol) indichloromethane (10 ml) was treated with oxalyl chloride (0.35 ml, 4mmol) and one drop of DMF at room temperature for 2 h. The solvent andexcess oxalyl chloride were removed in vacuo. The residue was dissolvedin toluene and the solvent again removed in vacuo.

The crude acid chloride was disolved in dry dichloromethane (10 ml) andtreated with silver cyanate (450 mg, 3 mmol) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (335 mg, 1 mmol).After stirring at room temperature for 1.5 h the title compound wasisolated by the procedure described in Example 31, Step 2, (310 mg,60%); ν_(max) (CH₂ Cl₂) 3388, 1775, 1748 and 1691 cm⁻¹ ; ¹ H NMR (CDCl₃)0.86 (3H, d, J6.8 Hz), 1.00 (3H, d, J6.4 Hz), 1.07-1.55 (6H, m), 1.21(3H, s), 1.24 (3H, s), 1.67 (1H, d, J15.5 Hz), 1.73 (1H, d, J11.5 Hz),2.02 (2H, m), 2.20 (1H, m), 2.50 (1H, dd, J15.3, 10.1 Hz), 2.89 (1H, q,J6.3 Hz), 3.23 (3H, s), 3.46 (1H, m), 4.15 (3H, s), 5.03 (1H, d, J17.5Hz), 5.34 (1H, d, J10.7 Hz), 5.76 (1H, d, J9.9 Hz), 6.69 (1H, dd, J17.5,10.7 Hz), 7.62 (1H, s), 7.65 (1H, d J15.5 Hz) 7.76 (1H, s), 7.84 (1H, d,J15.7 Hz); MS (NH₃ DCI) m/z 513 (MH⁺).

Step 4: (E)-Mutilin14-[N-3-(1-methyl-1,2,3-triazol-4-yl)acryloyl]-carbamate

The product from step 3, (272 mg) in dioxan (2 ml) was treated with asaturated solution of zinc chloride in conc. HCl (1 ml), as for Example1 Step 2, to afford the title compound, (173 mg, 65%); ν_(max) (CH₂ Cl₂)3390, 1777, 1735 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.76 (3H, d, J6.6 Hz), 0.89 (3H,d, J7.0 Hz), 1.18 (3H, s), 1.19 (1H, m), 1.45 (3H, s), 1.46 (3H, m),1.57-1.81 (2H, m), 1.62 (3H, s), 2.05-2.36 (5H, m), 3.37 (1H, dd, J10.7,6.6 Hz), 4.14 (3H, s), 5.24 (1H, dd, J17.4, 1.3 Hz), 5.40 (1H, dd,J11.1, 1.3 Hz), 5.75 (1H d, J8.4 Hz), 6.53 (1H, dd, J17.3, 11.0 Hz),7.54 (1H, s), 7.60 (1H, d, J15.7 Hz), 7.74 (1H, s), 7.81 (1H, d, J15.7Hz); MS (EI) m/z 498 (M⁺), (NH₃ DCI) m/z 516 (MH₄ ⁺), 499 (MH⁺), Found:498.2844, C₂₇ H₃₈ N₄ O₅ requires 498.2842.

EXAMPLE 128 Mutilin14-N-{[2-(N,N-Diethylamino)-ethylthio]-acetyl}-carbamate Hydrochloride

Mutilin 14-N-{[2-(N,N-diethylamino)ethylthio]acetyl}carbamate (110 mg,0.2 mmol) in methanol (4 ml) was treated with chlorotrimethylsilane (0.1ml) and the mixture was left to stand for 10 min. The solvents wereremoved. Chloroform was added and removed (×2). The residue wastriturated under diethyl ether, and the resultant solid was isolated byfiltration and then dried over P₂ O₅ in vacuo to give the title compound(70 mg, 59%), ν_(max) (KBr) 2926, 2674, 1770, 1728, 1512, 1506, 1453,and 1215 cm⁻¹ ; ¹ H NMR [(CD₃)₂ SO] 0.65 (3H, d, J 6.3 Hz), 0.82 (3H, d,J 6.7 Hz), 1.08 (4H, s at 1.07 superposed on m), 1.15-1.80 (ca. 16H, mincluding t, J 7.2 Hz at 1.20 and s at 1.40), 2.0-2.3 (ca. 3H, m), 2.41(1H, br s), 2.95-3.00 (2H, m), 3.05-3.18 (4H, m), 3.18-3.30 (2H, m),3.46 (1H, br t; d, J 5.4 after D₂ O exch.), 3.52 (2H, s), 4.57 (1H, d, J6.0 Hz, exch D₂ O), 5.04-5.15 (2H, m), 5.49 (1H, d, J 8.0 Hz), 6.21 (1H,dd, J 10.4, 17.7 Hz), 9.98 (1H, br s, exch D₂ O), and 10.64 (1H, s, exchD₂ O).

EXAMPLE 129 Mutilin 14-N-(Formyloxy-acetyl)-carbamate

Mutilin 14-N-(chloroacetyl)carbamate (110 mg, 0.25 mmol) and potassiumiodide (332 mg) in N,N-dimethyl-formamide (4 ml) was stirred for 10minutes and then treated with sodium formate (68 mg), followed by moreN,N-dimethylformamide (1 ml). The mixture was stirred for four days andthen ethyl acetate and water were added, and the aqueous layer wasre-extracted with ethyl acetate. The combined extracts were washed withbrine, dried (MgSO₄) and evaporated. The residue was chromatographed onsilica gel eluting with ethyl acetate hexane mixtures to give, afterevaporation of requisite fractions, the title compound (120 mg,quantitative), ν_(max) (CH₂ Cl₂) 3564, 3381, 2944, 1791(w), 1755 (sh),1739, 1724, 1472, 1393, 1214, 1160, 1116, 1016, 978, and 936 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.74 (3H, d, J 6.9 Hz), 0.90 (3H, d, J 7.0 Hz),1.20 (s), 1.42 (s), 3.37 (1H, dd, J 6.6, 10.6 Hz), 5.12 and 5.21 (2H,ABq J 17.2 Hz), 5.24 (1H, dd, J 1.4,17.5 Hz), 5.38 (1H, dd, J 1.3, 11.1Hz), 5.69 (1H, d, J8.5 Hz), 6.45 (1H, dd, J 11.1, 17.4 Hz), 7.67 (1H, brs), 8.06 (1H, s); MS(CI) m/z 467 (MNH₄ ⁺).

EXAMPLE 130 Mutilin 14-N-(Hydroxyacetyl)-carbamate

Mutilin 14-N-(formyloxyacetyl)carbamate (140 mg, 0.31 mmol) in methanol(5 ml) was stirred for 78 h and the methanol was then removed.Chromatography of the residue on silica gel, eluting with ethylacetate/hexane mixtures gave the title compound as a solid (58 mg, 44%),ν_(max) (CH₂ Cl₂) 3564, 3386, 2932, 1786(w), 1756, 1735, 1712, 1472, and1209 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 0.73 (3H, d, J 6.8 Hz), 0.89 (3H,d, J 7.1 Hz), 1.19 (s), 1.42 (s), 2.99 (1H, t, J 4.9 Hz), 3.37 (1H, dd,J 6.6, 10.6 Hz), 4.4-4.6 (2H, m), 5.22 (1H, dd, J 1.4, 17.5 Hz), 5.37(1H, dd, J 1.3, 11.1 Hz), 5.71 (1H, d, J 8.5 Hz), 6.45 (1H, dd, J 11.0,17.4 Hz), 7.81 (1H, br s); MS(ES+) m/z 534(M-H+TFA)⁺ ; MS(ES-) m/z 420(M-H)⁻.

EXAMPLE 131 Mutilin 14-N-(Iodoacetyl)-carbamate

Mutilin 14-N-(chloroacetyl)carbamate (400 mg, 0.91 mmol) in acetone (50ml) was treated with potassium iodide (1.2 g, 7.2 mmol), and the mixturewas stirred at room temperature for 5 days. Water and ethyl acetateswere added and the layers were separated. The ethyl acetate layer waswashed with brine, dried (MgSO₄) and evaporated. The crude product waschromatographed on silica gel, eluting with ethyl acetate/hexanemixtures to give the title compound (475 mg, 86%), ¹ H NMR (CDCl₃) 0.77(3H, d, J 6.7 Hz), 0.90 (3H, d, J 7.0 Hz), 1.0-1.3 (4H, m, including sat 1.20), 1.3-1.9 (12H, m, including s at 1.42), 2.0-2.4 (4H, m), 3.37(1H, dd, J 6.6, 10.5 Hz), 4.18 and 4.32 (2H, ABq J 9.6 Hz), 5.24 (1H,dd, J 1.4, 17.4 Hz), 5.39 (1H, dd, J 1.3, 10.9 Hz), 5.74 (1H, d, J 8.5Hz), 6.48 (1H, dd, J 11.0, 17.4 Hz), 7.47 (1H, s).

EXAMPLE 132 Mutilin 14-N-(Azidoacetyl)-carbamate

Mutilin 14-N-(iodoacetyl)carbamate (133 mg, 0.25 mmol) and sodium azide(16 mg, 0.25 mmol) were stirred together in N,N-dimethyl-formamide for24 h. Ethyl acetate and water were added and the layers separated. Theaqueous layer was re-extracted with ethyl acetate and combined ethylacetate layers were washed with brine, dried (MgSO₄) and evaporated.Chromatography on silica gel, eluting with ethyl acetate/hexane 6:4, andevaporation of requisite fractions, gave the title compound (101 mg,90%), ν_(max) (CH₂ Cl₂) 3381, 2931, 2111, 1789(w), 1755, 1724, 1470, and1206 cm⁻¹ ; ¹ H NMR (CDCl₃) 0.73 (3H, d, J 6.7 Hz), 0.89 (3H, d, J 7.0Hz), 1.0-1.3 (4H,m, including s at 1.19), 1.3-1.9(12H,m, including s at1.43), 2.0-2.4 (4H, m), 3.36 (1H, dd, J 6.6, 10.6 Hz), 4.31 and 4.40(2H, ABq J 18.3 Hz), 5.23 (1H, dd, J 1.4, 17.4 Hz), 5.37 (1H, dd, J 1.3,11.1 Hz), 5.69 (1H, d, J 8.5 Hz), 6.45 (1H, dd, J 11.0, 17.4 Hz), 7.72(1H, s); MS(ES-) m/z 445 (M-H⁻).

EXAMPLE 133 Mutilin 14-N-[2-(3-Hydroxypyrid-2-ylthio)-acetyl]-carbamate

Mutilin 14-N-(chloroacetyl)carbamate (110 mg, 0.25 mmol) inN,N-dimethyl-formamide (4 ml) was treated with potassium iodide (166 mg,1 mmol). After 10 min 3-hydroxy-2-mercaptopyridine (35 mg, 0.275 mmol)and potassium carbonate (35 mg, 0.25 mmol) and N,N-dimethylformamide (1ml) were added. The mixture was stirred for 24 h and then added to ethylacetate/water. After separation the aqueous layer was re-extracted withethyl acetate. The combined ethyl acetate layers were dried (MgSO₄) andevaporated. The residue was chromatographed on silica gel, eluting withethyl acetate/hexane mixtures to yield the title compound (110 mg, 83%);ν_(max) (KBr) 2956, 1782, 1725, 1711, 1523, 1491, 1449, and 1299 cm⁻¹ ;¹ H NMR [(CD₃)₂ SO] 0.66 (3H, d, J 6.1 Hz), 0.82 (3H, d, J 6.7 Hz),0.9-1.8 (ca 15H, m, including s at 1.14 and s at 1.39), 2.0-2.3 (4H, m),2.41 (1H, br s), 3.44 (1H, br t, d, J 5.4 Hz after D₂ O exch), 4.04 (2H,s), 4.53 (1, d J 6.0 Hz, exch D₂ O) 5.04-5.15 (2H,m), 5.50 (1H, d, J 7.9Hz), 6.22 (1H, dd, J 11.1, 17.7 Hz), 6.94-7.06 (2H, m), 7.83 (1H, dd J1.4 and 4.6 Hz), 10.43 (1H, br s, exch. D₂ O), 10.65 (1H, s, exch. D₂O); MS(CI) m/z 531 (M+H)⁺.

EXAMPLE 134 Mutilin14-N-[2-(4-Methylpyrimidin-2-ylthio)-acetyl]-carbamate

Using a similar procedure to that described in Example 133,2-mercapto-4-methylpyrimidine (42 mg, 0.26 mmol) was converted over 3days into the title compound (95 mg, 71%), ν_(max) (CH₂ Cl₂) 3377, 3179,2961, 1782(w), 1734, 1576, 1545, 1332, 1217, 1116, and 1016 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.61 (3H, d, J 6.5 Hz), 0.87 (3H, d, J 7.0 Hz),1.19 (s, 1.43 (s), 2.51 (3H, s), 3.34 (1H, dd, J 6.6, 11.1 Hz), 3.84 and3.92 (2H, ABq J 15.1 Hz), 5.22 (1H, dd, J 1.4, 17.3 Hz), 5.37 (1H, dd, J1.4, 10.9 Hz), 5.71 (1H, d, J 8.5 Hz), 6.54 (1H, dd, J 11.0, 17.4 Hz),6.96 (1H, d J 5.1 Hz), 8.41 (1H, d J 5.2 Hz), 9.57 (1H, br s) ; MS(EI)m/z 589 (M⁺); Found: 529.2607, C₂₈ H₃₉ N₃ O₅ S requires 529.2610.

EXAMPLE 135 Mutilin 14-N-[2-(1-Oxopyrid-2-ylthio)-acetyl]-carbamate

Using a similar procedure to that described in Example 133,2-mercaptopyridine-1-oxide (32 mg, 0.25 mmol) was converted in 3 daysinto the title compound (87 mg, 65%), ν_(max) (CH₂ Cl₂) 3386, 2962,2932, 1783, 1734, 1484, 1204, 1116, and 1016 cm⁻¹ ; ¹ H NMR (CDCl₃)inter alia 0.72 (3H, d, J 6.7 Hz), 0.89 (3H, d, J 7.0 Hz), 1.18 (s),1.42 (s), 3.36 (1H, dd, J 6.6, 10.5 Hz), 4.06 (2H, s), 5.24 (1H, dd, J1.3, 17.4 Hz), 5.41 (1H, dd, J 1.3, 11.0 Hz), 5.73 (1H, d, J 8.4 Hz),6.50 (1H, dd, J 11.0, 17.4 Hz), 7.3 (1H, dt J 1.7, 6.5 Hz), 7.27 (1H,dt, J ca. 1.2, 8 Hz) 7.51 (1H, dd J 1.7, 8.2 Hz), 8.27 (1H, dd, J 0.9,6.4), 8.36 (1H, br s); MS(CI) m/z 531 (MH)⁺.

EXAMPLE 136 Mutilin 14-N-(Ethylthio-acetyl)-carbamate

Using a similar procedure to that described in Example 133, thechloroacetyl compound (280 mg, 0.64 mmol) and sodium ethane thiolate (79mg), with no potassium carbonate, was converted in 26 hours into thetitle compound (194 mg, 65%), ν_(max) (CH₂ Cl₂) 3386, 2962, 2932, 1782,1756 (sh),1734, 1716 (sh), 1484, 1204, 1116, and 1016 cm⁻¹ ; ¹ H NMR(CDCl₃) inter alia 0.76 (3H, d, J 6.7 Hz), 0.89 (3H, d, J 7.1 Hz), 1.18(s), 1.26 (t, J 7.4 Hz), 1.44 (s), 2.56 (2H, q, J 7.4 Hz), 3.36 (1H, dd,J 6.6, 11.7 Hz), 3.51 and 3.60 (2H, ABq, J 15.2 Hz), 5.22 (1H, dd, J1.5, 17.4 Hz), 5.38 (1H, dd, J 1.4, 10.9 Hz), 5.73 (1H, d, J 8.5 Hz),6.51 (1H, dd, J 11.0, 17.3 Hz), 7.95 (1H, br s); MS(CI) m/z 483 (MNH₄)⁺.

EXAMPLE 137 Mutilin 14-N-(Ethylsulfinyl-acetyl)-carbamate

Mutilin 14-N-(ethylthio-acetyl)carbamate (74 mg, 0.16 mmol) indichloromethane (4 ml) was cooled in an ice-bath and treated withm-chloroperbenzoic acid (55% pure, 50 mg, 0.16 mmol) and the mixture wasstirred for 2 h. The mixture was diluted with dichloromethane and washedwith aqueous NaHCO₃, dried (MgSO₄) and evaporated. The residue waschromatographed on silica gel, eluting with ethyl acetate/hexanemixtures to give the title compound as a mixture of diasteroisomericsulphoxides (57 mg, 73%), ν_(max) (CH₂ Cl₂) 3380, 2940, 2932,1781, 1735,1518, 1470, 1211, 1116, 1014, and 910 cm⁻¹ ; MS(ES-) m/z 480 (M-H)⁻.

EXAMPLE 138 Mutilin 14-N-(Ethylsulfonyl-acetyl)-carbamate

The Mutilin 14-N-(ethylthio-acetyl)carbamate (74 mg, 0.16 mmol) indichloromethane (4 ml) was cooled in an ice-bath and treated withm-chloroperbenzoic acid (55% pure, 100 mg, 0.32 mmol) and the mixturewas stirred for 2 h. The mixture was diluted with dichloromethane andwashed with dilute aqueous NaHCO₃ dried (MgSO₄) and evaporated. Theresidue was chromatographed on silica gel, eluting with ethylacetate/hexane mixtures to give the title compound (36 mg, 45%), ν_(max)(CH₂ Cl₂) 3373, 2944, 1787, 1757, 1733, 1706, 1469, 1324, 1208, 1153,1116, 1016, 939, and 910 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 0.75 (3H, d,J 6.8 Hz), 0.89 (3H, d, J 7.0 Hz), 1.18 (s), 3.25 (2H, q, J 7.5 Hz),3.37 (1H, dd, J 6.7, 9.8 Hz), 4.50 (2H, br ABq), 5.24 (1H, dd, J 1.3,17.3 Hz), 5.37 (1H, dd, J 1.3, 10.9 Hz), 5.71 (1H, d, J 8.4 Hz), 6.47(1H, dd, J 11.1, 17.4 Hz), 8.19 (1H, br s); MS(ES-) m/z 496 (M-H)⁻.

EXAMPLE 139 Mutilin14-N-[tert-Butyloxycarbonylmethylthioacetyl]-carbamate

Mutilin 14-N-(chloroacetyl)carbamate (55 mg, 0.125 mmol) inN,N-dimethyl-formamide (2 ml) was treated with potassium iodide (84 mg,0.5 mmol) and potassium carbonate (18 mg, 0.125 mmol). tert-Butyl2-mercaptoacetate (18.5 mg, 0.125 mmol) in N,N-dimethyl-formamide (0.5ml) was then added. The mixture was shaken for 17 h and then treatedwith ethyl acetate (5 ml)/water (7.5 ml). After separation the ethylacetate layer was washed with 1M NaOH and dried (MgSO₄) and evaporated.The residue was chromatographed on silica gel, eluting with ethylacetate/hexane mixtures to yield the title compound (44 mg, 63%), ¹ HNMR (CDCl₃) inter alia 0.76 (3H, d, J 6.7 Hz), 0.88 (3H, d, J 7.0 Hz1.18 (s), 1.44 (s), 1.47 (s), 3.26 (2H, s), 3.36 (1H, dd, J 6.6, 10.8Hz), 3.64 (2H, br s), 5.22 (1H, dd, J 1.4, 17.3 Hz), 5.37 (1H, dd, J1.3, 11.0 Hz), 5.71 (1H, d, J 8.4 Hz), 6.51 (1H, dd, J 11.0, 17.3 Hz),8.35 (1H, br s).

EXAMPLE 140 Mutilin14-N-[2-(Ethyloxycarbonyl)ethylthio-acetyl]-carbamate

Using the process described in Example 139 mutilin14-N-(chloroacetyl)-carbamate (55 mg, 0.125 mmol) and ethyl3-mercaptopropionate (16.8 mg, 0.125 mmol) were converted into the titlecompound (51 mg, 75%), ¹ H NMR (CDCl₃) inter alia 0.75 (3H, d, J 6.7Hz), 0.88 (3H, d, J 7.0 Hz), 1.19 (s), 1.26 (t, J 7.2 Hz), 1.44 (s),2.62 (2H, t, J 6.8 Hz), 2.84 (2H, t, J 6.7 Hz), 3.36 (1H, dd, J 6.6,10.6 Hz), 3.56 and 3.64 (2H, ABq, J 15.0 Hz), 5.22 (1H, dd, J 1.4, 17.3Hz), 5.37 (1H, dd, J 1.3, 11.0 Hz), 5.71 (1H, d, J 8.4 Hz), 6.48 (1H,dd, J 11.0, 17.3 Hz), 7.90 (1H, br s).

EXAMPLE 141 Mutilin14-N-[(5-Methyl-1,3,4-thiadiazol-2-ylthio)-acetyl]-carbamate

Using the process described in Example 139 mutilin14-N-(chloroacetyl)-carbamate (55 mg, 0.125 mmol) and2-mercapto-5-methyl-1,3,4-thiadiazole (16.5 mg, 0.125 mmol) wereconverted into the title compound (38 mg, 56%), ¹ H NMR (CDCl₃) interalia 0.65 (3H, d, J 6.7 Hz), 0.88 (3H, d, J 7.0 Hz), 1.18 (s), 1.42 (s),2.74 (s, 3H), 3.35 (1H, dd, J 6.6, 10.9 Hz), 4.14 and 4.33 (2H, ABq, J15.5 Hz), 5.22 (1H, dd, J 1.4, 17.3 Hz), 5.38 (1H, dd, .J 1.4, 11.0 Hz),5.70 (1H, d, J 8.4 Hz), 6.53 (1H, dd, J 11.0, 17.3 Hz), 9.05 (1H, br s).

EXAMPLE 142 Mutilin 14-N-[(1-Methyltetrazol-5-ylthio)-acetyl]-carbamate

Using the process described in Example 139 mutilin14-N-(chloroacetyl)-carbamate (55 mg, 0.125 mmol) and5-mercapto-1-methyl-tetrazole (14.5 mg, 0.125 mmol) were converted intothe title compound (28 mg, 43%), ¹ H NMR (CDCl₃) inter alia 0.71 (3H, d,J 6.7 Hz), 0.89 (3H, d, J 6.9 Hz), 1.19 (s), 1.41 (s), 3.36 (1H, dd, J6.6, 10.7 Hz), 3.98 (3H, s), 4.46 and 4.54 (2H, ABq, J 16.8 Hz), 5.24(1H, dd, J 1.4, 17.4 Hz), 5.39 (1H, dd, J 1.3, 11.1 Hz), 5.71 (1H, d, J8.4 Hz), 6.49 (1H, dd, J 11.0, 17.3 Hz), 8.44 (1H, br s).

EXAMPLE 143 Mutilin 14-N-[(1-Phenyl-tetrazol-5-ylthio)-acetyl]-carbamate

Using the process described in Example 139 mutilin14-N-(chloroacetyl)-carbamate (55 mg, 0.125 mmol) and5-mercapto-1-phenyl-tetrazole (22.3 mg, 0.125 mmol) were converted intothe title compound, (60 mg, 82%), ¹ H NMR (CDCl₃) inter alia 0.72 (3H,d, J 6.7 Hz), 0.89 (3H, d, J 7.0 Hz), 1.20 (s), 1.44 (s), 3.37 (1H, dd,J 6.6, 10.8 Hz), 4.50 and 4.60 (2H, ABq, J 16.6 Hz), 5.24 (1H, dd, J1.4, 17.4 Hz), 5.38 (1H, dd, 1.3, 11.0 Hz), 5.73 (1H, d, J 8.7 Hz), 6.50(1H, dd, J 11.0, 17.4 Hz), 7.58 (5H, s), 8.39 (1H, br s).

EXAMPLE 144 Mutilin 14-N-[(1,3,4-Thiadiazol-2-ylthio)-acetyl]-carbamate

Using the process described in Example 139 mutilin14-N-(chloroacetyl)-carbamate (55 mg, 0.125 mmol) and2-mercapto-1,3,4-thiadiazole (14.9 mg, 0.125 mmol) were converted intothe title compound (37 mg, 60%), ¹ H NMR (CDCl₃) inter alia 0.67 (3H, d,J 6.7 Hz), 0.88 (3H, d, J 6.9 Hz), 1.19 (s), 1.42 (s),3.36 (1H, dd, J6.5, 10.9 Hz), 4.29 and 4.47 (2H, ABq, J 15.8 Hz), 5.24 (1H, d, J 17.3Hz), 5.38 (1H, d, J 12.0 Hz), 5.70 (1H, d, J 8.4 Hz), 6.51 (1H, dd, J11.0, 17.4 Hz), 8.77 (1H, br s), 9.13 (1H, s).

EXAMPLE 145 Mutilin14-N-[(5-Aminocarbonyl-1,3,4-thiadiazol-2-ylthio)-acetyl]-carbamate

Using the process described in Example 139 mutilin14-N-(chloroacetyl)-carbamate (55 mg, 0.125 mmol) and2-mercapto-1,3,4-thiadiazole-5-carbamate (16.1 mg, 0.125 mmol) wereconverted into the title compound (21 mg, 29%), 1H NMR (CDCl₃) interalia 0.67 (3H, d, J 6.7 Hz), 0.88 (3H, d, J 7.0 Hz), 1.19 (s), 1.42 (s),3.36 (1H, dd, J 6.5, 10.8 Hz), 4.29 and 4.47 (2H, ABq, J 15.8 Hz), 5.24(1H, d, J 17.5 Hz), 5.39 (1H, d, J 10.9 Hz), 5.71 (1H, d, J 8.4 Hz),5.86 (1H, s), 6.51 (1H, dd, J 11.0, 17.3 Hz), 7.10 (1H, s), 8.48 (1H, brs).

EXAMPLE 146 Mutilin14-N-[(5-Aminocarbonyl-1,3,4-oxadiazol-2-ylthio)-acetyl]-carbamate

Using the process described in Example 139 mutilin14-N-(chloroacetyl)-carbamate (55 mg, 0.125 mmol) and2-mercapto-1,3,4-oxadiazole-5-carbamate (20.1 mg, 0.125 mmol) wereconverted into the title compound (8 mg, 11%), ¹ H NMR (CDCl₃) interalia 0.73 (3H, d, J 6.8 Hz), 0.90 (3H, d, J 6.8 Hz), 1.19 (s), 1.43(s),3.37 (1H, dd), 4.54 and 4.61 (2H, ABq, J 17.0 Hz), 5.25 (1H, dd, J1.3, 17.4 Hz), 5.39 (1H, dd, J 1.2, 11.0 Hz), 5.72 (1H, d, J 8.4 Hz),6.01 (1H, br s), 6.48 (1H, dd, J 11.1, 17.4 Hz), 7.01 (1H, br s), 8.21(1H, br s).

EXAMPLE 147 Mutilin14-N-[1-(2-Dimethylaminoethyl)-tetrazol-5-ylthio]-acetyl}-carbamate

Mutilin 14-N-(iodoacetyl)carbamate (133 mg, 0.25 mmol) inN,N-dimethyl-formamide (2 ml) was treated with potassium carbonate (35mg, 0.25 mmol) and 1-(2-dimethylaminoethyl)-5-mercaptotetrazole (43 mg,0.25 mmol). The mixture was shaken for 17 h and then treated with ethylacetate (5 ml)/water (5 ml). After separation the aqueous layer wasre-extracted with ethyl acetate (5 ml). The combined ethyl acetatelayers were washed with brine, and dried (MgSO₄) and evaporated. Theresidue was chromatographed on silica gel, eluting with ethylacetate/hexane mixtures to yield the title compound (96 mg, 66%),ν_(max) (CH₂ Cl₂) 3384, 2948, 1782, 1733, 1468, 1390, 1215, 112, 1116,1016, and 938 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 0.68 (3H, d, J 6.7 Hz),0.87 (3H, d, J 7.0 Hz), 1.17 (s), 1.42 (s), 2.23 (s), 2.73 (2H, t, J 6.2Hz), 3.34 (1H, dd, J 6.5, 10.5 Hz), 4.33 (4H, t J 6.1 Hz), 5.21 (1H, dd,J 1.3, 17.3 Hz), 5.37 (1H, dd, J 1.3, 11.0 Hz), 5.69 (1H, d, J 8.4 Hz),6.49 (1H, dd, J 11.0, 17.4 Hz), 8.68 (1H, br s); MS(EI) m/z 576 (M⁺);Found: 576.3072, C₂₈ H₄₄ N₆ O₅ S req. 576.3094.

EXAMPLE 148 Mutilin 14-N-[(1,2,3-Triazol-5-ylthio)-acetyl]-carbamate

Using the process described in Example 147 mutilin14-N-(iodoacetyl)-carbamate (133 mg, 0.25 mmol) and the sodium salt of5-mercapto-1,2,3-triazole (31 mg, 0.25 mmol), in the absence ofpotassium carbonate, were converted into the title compound (75 mg,55%), ν_(max) (CH₂ Cl₂) 3408, 3220, 2930, 1781, 1733, 1471, 1410, 1387,1209,1116, and 1016 cm¹ ; ¹ H NMR (CDCl₃) inter alia 0.70 (3H, d, J 6.7Hz), 0.87 (3H, d, J 7.0 Hz), 1.17 (s), 1.42 (s), 3.35 (1H, br s), 3.93(2H, s),5.21 (1H, dd, J 1.3, 17.4 Hz), 5.35 (1H, dd, J 1.2, 11.1 Hz),5.69 (1H, d, J 8.4 Hz), 6.49 (1H, dd, J 11.0, 17.4 Hz), 7.67 (1H, s),8.65 (1H, br s); MS(CI) m/z 522 (MNH₄)⁺.

EXAMPLE 149 Mutilin14-N-{[1-(Methoxycarbonylmethyl)-tetrazol-5-ylthio]-acetyl}-carbamate

Using the process described in Example 147 mutilin14-N-(iodoacetyl)-carbamate (133 mg, 0.25 mmol) and methyl5-(mercapto-tetrazol-1-yl)-acetate (44 mg, 0.25 mmol) were convertedinto the title compound (77 mg, 53%), ν_(max) (CH₂ Cl₂) 3380, 2958,1783, 1759, 1733, 1459,1217, 1183, 1116, 1016, and 939 cm⁻¹ ; ¹ H NMR(CDCl₃) inter alia 0.69 (3H, d, J 6.8 Hz), 0.87 (3H, d, J 7.0 Hz), 1.17(s), 1.41 (s), 3.35 (1H, dd, J 6.5, 10.7 Hz), 4.46 and 4.56 (2H, ABq J16.9 Hz), 5.13 (2H, s), 5.22 (1H, dd, J 1.3, 17.3 Hz), 5.37 (1H, dd, J1.3, 11.1 Hz), 5.69 (1H, d, J 8.4 Hz), 6.47 (1H, dd, J 11.0, 17.4 Hz),8.26 (1H, br s); MS(CI) m/z 595 (MNH₄)⁺.

EXAMPLE 150 Mutilin14-N-{[3-(Methoxycarbonyl)-pyrid-2-ylthio]-acetyl}-carbamate

Using the process described in Example 147 mutilin14-N-(iodoacetyl)-carbamate (133 mg, 0.25 mmol) and methyl methyl2-mercapto-pyridine-3-carboxylate (42 mg, 0.25 mmol) were converted intothe title compound (48 mg, 33%), ν_(max) (CH₂ Cl₂) 3380, 2956, 1781,1720, 1401, 1214, 1139, 1116, 1071, and 1016 cm⁻¹ ; ¹ H NMR (CDCl₃)inter alia 0.55 (3H, d, J 6.6 Hz), 0.84 (3H, d, J 7.0 Hz 1.14 (s), 1.36(s), 3.31 (1H, dd, J 6.6, 11.0 Hz), 3.91 (2H, s), 3.94 (3H, s), 5.21(1H, dd, J 1.4, 17.3 Hz), 5.35 (1H, dd, J 1.4, 10.9 Hz), 5.65 (1H, d, J8.5 Hz), 6.47 (1H, dd, J 11.0, 17.4 Hz), 7.20 (1H, dd J 5.0, 7.8 Hz),8.30 (1H, dd J 1.8, 7.8 Hz), 8.55 (1H, dd, J 1.7, 4.8 Hz), 9.45 (1H, brs); MS(CI) m/z 573 (MH)⁺.

EXAMPLE 151 Mutilin 14-N-[(2-Furylmethylthio)-acetyl]-carbamate

Using the process described in Example 147 mutilin14-N-(iodoacetyl)-carbamate (133 mg, 0.25 mmol) and (2-furyl)-methylmercaptan (29 mg, 0.25 mmol) were converted into the title compound (43mg, 53%), ν_(max) (CH₂ Cl₂) 3382, 2930, 1783, 1734, 1483, 1206, 1152,1116, 1014, and 938 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 0.73 (3H, d, J 6.6Hz), 0.87 (3H, d, J 7.0 Hz), 1.18 (s), 1.42 (s), 3.35 (1H, dd, J 6.7,10.7 Hz), 3.48 and 3.56 (2H, ABq J 15.7 Hz), 3.76 (2H, s), 5.21 (1H, dd,J 1.4, 17.3 Hz), 5.36 (1H, dd, J 1.3, 11.1 Hz), 5.70 (1H, d, J 8.4 Hz),6.21 (1H, d, J 3.4 Hz), 6.28 (1H, J d 1.9, 5.01 Hz), 6.48 (1H, dd, J11.0, 17.4 Hz), 7.34 (1H, dd J 0.8, 1.9 Hz), 7.80 (1H, br s); MS(CI) m/z535 (MNH₄)⁺.

EXAMPLE 152 Mutilin 14-N-[(2,3-Dihydroxypropylthio)-acetyl]-carbamate

Using the process described in Example 147 mutilin14-N-(iodoacetyl)-carbamate (133 mg, 0.25 mmol) and3-mercapto-1,2-propane-diol (0.021 ml, 27 mg, 0.25 mmol) were convertedinto the title compound (37 mg, 28%); ν_(max) (CH₂ Cl₂) 3380, 2929,1782, 1733, 1471, 1409, 1206, 1115, and 1016 cm⁻¹ ; ¹ H NMR (CDCl₃)inter alia 0.74 (3H, d, J 6.5 Hz), 0.87 (3H, d, J 7.0 Hz), 1.17 (s),1.42 (s), 2.56-2.81 (2H,m), 3.12 (1H, s, exch. D₂ O), 3.35 (1H, dd, J6.6, 10.5 Hz; d, J 6.4 after D₂ O exch.), 3.50-3.58 (1H, m), 3.96-4.11(2H, m), 4.13-4.21 (1H, m), 5.21 (1H, dd, J 1.3, 17.4 Hz), 5.36 (1H, d,J 11.1 Hz), 5.69 (1H, d, J 8.4 Hz), 6.47 (1H, dd, J 11.0, 17.4 Hz), 7.99(1H, br s); MS(ES+) m/z 529 (MNH₄)⁺.

EXAMPLE 153 Mutilin 14-N-[(Pyrid-2-ylthio)-acetyl]-carbamate

Using the process described in Example 147 mutilin14-N-(iodoacetyl)-carbamate (133 mg, 0.25 mmol) and 2-mercapto-pyridine(28 mg, 0.25 mmol) were converted into the title compound (107 mg, 83%),ν_(max) (CH₂ Cl₂) 3557, 3379, 3151, 2932, 1779, 1733, 1584, 1527, 1456,1417, 1220, 1152, 1116, 1034, and 1016 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia0.56 (3H, d, J 6.4 Hz), 0.84 (3H, d, J 7.0 Hz), 1.14 (s), 1.38 (s), 3.32(1H, d, J 6.5, Hz), 3.70 and 3.84 (2H, ABq, J 14.5 Hz), 5.19 (1H, dd, J1.5, 17.4 Hz), 5.35 (1H, dd, J 1.5, 10.9 Hz), 5.65 (1H, d, J 8.6 Hz),6.57 (1H, dd, J 10.9, 17.3 Hz), 7.06-7.16 (1H, m), 7.24-7.30 (2H, m),7.55 (1H, m), 8.42-8.45 (1H, m), 10.71 (1H, br s); MS(EI) m/z 514 (M⁺);Found: 514.2485, C₂₈ H₃₈ N₂ O₅ S requires 514.2501.

EXAMPLE 154 Mutilin 14-N-[(Cyanothio)-acetyl]-carbamate

Using the process described in Example 147 mutilin14-N-(iodoacetyl)-carbamate (133 mg, 0.25 mmol) and ammonium thiocyanate(19 mg, 0.25 mmol), in the absence of potassium carbonate, wereconverted into the title compound (105 mg, 90%), ν_(max) (CH₂ Cl₂) 3376,2931, 1752, 1735, 1721, 1472, 1216, 1188, 1116, 1016, and 939 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 0.72 (3H, d, J 6.9 Hz), 0.88 (3H, d, J 7.0 Hz),1.18 (s), 1.41 (s), 3.36 (1H, dd, J 6.6, 10.4 Hz), 4.37 (2H, s), 5.23(1H, dd, J 1.3, 17.3 Hz), 5.38 (1H, dd, J 1.2, 10.9 Hz), 5.68 (1H, d, J8.5 Hz), 6.41 (1H, dd, J 11.0, 17.4 Hz), 7.94 (1H, br s); MS(ES-) m/z461 (M-H)⁻.

EXAMPLE 155 Mutilin 14-N-[N-Acetylglycyl]carbamate

Mutilin 14-N-(azidoacetyl)carbamate (113 mg, 0.25 mmol) in drytetrahydrofuran (1 ml) under argon was treated with tri-n-butylphosphine(0.045 ml, 55 mg, 0.275 mmol) and the mixture was stirred under argonfor 1 h. The solution was then cooled to -50° C. and acetyl chloride(0.024 ml, 21 mg, 0.275 mmol) was added. The mixture was stirred for 45min and then saturated aqueous NaHCO₃ (0.5 ml) was added and the mixturewas allowed to warm to room temperature. Ethyl acetate and brine wereadded, the layers were separated and the ethyl acetate layer was dried(MgSO₄)and evaporated. The residue was chromatographed on silica gel,eluting with ethyl acetate hexane mixtures to give the title compound(20 mg, 17%), ν_(max) (CH₂ Cl₂) 3427, 3385, 2961, 2935, 1783, 1756,1732, 1674, 1509, and 1474 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 0.71 (3H,d, J 6.8 Hz), 0.87 (3H, d, J 7.0 Hz), 1.17 (s), 1.41 (s), 2.04 (s), 2.54(1H, br d J 6.0 Hz), 4.38 and 4.47 (2H, dABq, J 4.9 and 19 Hz), 5.21(1H, dd, J 1.1, 17.3 Hz), 5.36 (1H, dd, J 1.1, 10.9 Hz), 5.68 (1H, d, J8.4 Hz), 6.26 (1H, br t, J ca. 4.6 Hz), 6.46 (1H, dd, J 11.1, 17.4 Hz),8.06 (1H, br s); (MS) (ES-) 461 (M-H)⁻.

EXAMPLE 156 Mutilin 14-N-(N,N-Diethylglycyl)carbamate

Mutilin 14-N-(iodoacetyl)carbamate (133 mg, 0.25 mmol) in diethylether(1.5 ml) was treated with diethylamine (0.03 ml). After 2 h and 6 hfurther aliquots of diethylamine (0.03 ml) were added and stirring wascontinued for a further 17 h. Ethyl acetate/water were added followed by1M NaOH (2ml). The aqueous layer was re-extracted with ethyl acetate,and combined ethyl acetate layers were dried (MgSO₄). and evaporated.Chromatography on silica gel, eluting with ethyl acetate/hexane 6:4, andevaporation of requisite fractions gave the title compound (103 mg,83%), MS(CI) m/z 477 (MH)⁺.

EXAMPLE 157 Mutilin14-{N-[(1-Methyl-1,2,3-triazol-4-yl)-carbonyl]-carbamate}

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[(1-methyl-1,2,3-triazol-4-yl)carbonyl]carbamate)

1-Methyl-1,2,3-triazole-4-carboxylic acid (2.00 g) in dichloromethane(50 ml) at room temperature was treated with oxalyl chloride (2.40 g)and two drops of DMF for 3 h. IR analysis showed complete conversion tothe acid chloride. The solvent and excess oxalyl chloride were removedin vacuo and the residue was re-evaporated from toluene to yield theacid chloride as a white solid.

The acid chloride (0.436 g), silver cyanate (0.450 g) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.334 g) were thensuspended in dry dichloromethane (5 ml) and stirred at room temperaturefor 4 h. The resulting suspension was filtered through Celite, washingwell with dichloromethane. The organic solution was washed with water,saturated sodium chloride solution and dried (MgSO₄). After filtration,the solvent was evaporated to yield the crude product Purification bysilica gel chromatography, eluting with ethyl acetate-hexane mixtures,provided the pure product as a colourless foam, (0.486 g); ¹ H NMR(CDCl₃) 0.90 (3H, d, J6.9 Hz), 1.00 (3H, d, J6.4 Hz), 1.05-1.80 (m),1.21 (3H, s) 1.30 (3H, s), 1.90-2.10 (2H, m), 2.14-2.28 (1H, m) 2.52(1H, dd, J10.1, 15.3 Hz), 2.90 (1H, q, J6.4 Hz), 3.24 (3H, s), 3.40-3.55(1H, m), 4.20 (3H, s), 5.00 (1H, d, J17.5 Hz), 5.30 (1H, d, J10.8 Hz),5.83 (1H, d, J 9.9 Hz), 6.78 (1H, dd, J10.7,17.5 Hz), 8.20 (1H, s) and9.10 (1H, s).

Step 2. Mutilin 14-{N-[(1-Methyl-1,2,3-triazol-4-yl)carbonyl]carbamate}

The product from step 1, (0.450 g) in 1,4-dioxan (4 ml) was stirred atroom temperature for 8 h with Lukas reagent (1.25 ml). The solution wasthen diluted with ethyl acetate and neutralized with saturated sodiumhydrogen carbonate solution. The organic solution was washed withsaturated sodium chloride solution, dried (MgSO₄) and evaporated toyield the crude product. After purification by silica gelchromatography, the title compound was isolated as a white solid, (0.405g); ¹ H NMR (CDCl₃) 0.79 (3H, d, J6.5 Hz), 0.89 (3H, d, J7.0 Hz), 1.20(3H, s), 1.40-1.90 (m), 1.52 (3H, s), 2.08-2.45 (5H, m), 3.39 (1H, dd,J6.6,11.0 Hz), 4.19 (3H, s), 5.22 (1H, dd, J3.5,17.4 Hz), 5.39 (1H, dd,J1.4,10.9 Hz), 5.83 (1H, d, J8.4 Hz), 6.59 (1H, dd, J10.95,17.3 Hz) 8.19(1H, s) and 9.03 (1H, s); MS (NH₄ DCI) m/z 490 (MNH₄ ⁺), 473 (MH⁺).

EXAMPLE 158 Mutilin 14-{N-[(1,2,3-thiadiazol-4-yl)-carbonyl]carbamate}

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[(1,2,3-thiadiazol-4-yl)-carbonyl]carbamate}

1,2,3-Thiadiazole-4-carboxylic acid was converted to the acid chlorideand reacted with (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin(0.334 g) as described for Example 157. Following purification by silicagel chromatography the title compound was obtained as a colourless foam(0.490 g); ¹ H NMR (CDCl₃) 0.90 (3H, d, J6.9 Hz), 1.00 (3H, d, J6.4 Hz),1.05-1.68 (m), 1.21 (3H, s), 1.30 (3H, s), 1.7-1.82 (2H, m), 1.92-2.10(2H, m), 2.14-2.28 (1H, m) 2.58 (1H, dd, J10.1,15.3 Hz), 2.90 (1H, q,J6.3 Hz), 3.25 (3H, s), 3.40-3.55 (1H, m), 5.02 (1H, d, J17.5 Hz), 5.32(1H, d, J10.0 Hz), 5.89 (1H, d, J 9.9 Hz), 6.77 (1H, dd, J 10.6,17.5Hz), 9.42 (1H, s) and 9.43 (1H, s).

Step 2. Mutilin 14-{N-[(1,2,3-thiadiazol-4-yl)carbonyl]carbamate}

The product from step 1, (0.460 g) in 1,4-dioxan (4 ml) was stirred atroom temperature for 7 h with Lukas reagent (1.25 ml). The solution wasthen diluted with ethyl acetate and neutralized with saturated sodiumhydrogen carbonate solution. The organic solution was washed withsaturated sodium chloride solution, dried (MgSO₄) and evaporated toyield the crude product. After purification by silica gelchromatography, the title compound was isolated as a white solid, (0.359g); ¹ H NMR (CDCl₃) 0.81 (3H, d, J6.7 Hz), 0.90 (3H, d, J7.0 Hz), 1.20(3H, s), 1.38-1.88 (m), 1.55 (3H, s), 2.10-2.45 (5H, m), 3.39 (1H, dd,J6.6,10.9 Hz), 5.22 (1H, dd, J1.5,17.2 Hz), 5.40 (1H, dd, J1.4,11.1 Hz),5.89 (1H, d, J8.5 Hz), 6.59 (1H, dd, J11.05,17.4 Hz) and 9.40 (2H, s):MS (NH₄ DCI) m/z 493 (MNH₄ ⁺).

EXAMPLE 159 Mutilin14-{N-[(1-ethyl-5-methylpyrazol-3-yl)-carbonyl]carbamate}

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[(1-ethyl-5-methylpyrazol-3-yl)carbonyl]carbamate}

1-Ethyl-5-methylpyrazole-3-carboxylic acid was converted to the acidchloride and reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.334 g) asdescribed for Example 157. Following purification by silica gelchromatography the title compound was obtained as a colourless foam(0.140 g); ¹ H NMR (CDCl₃) 0.90 (3H, d, J6.9 Hz), 1.00 (3H, d, J6.4 Hz),1.05-1.64 (m), 1.20 (3H, s), 1.37 (3H, s), 1.42 (3H, t, J7.3 Hz),1.71(1H, d, J5.5 Hz), 1.79 (1H, s) 1.95-2.10 (2H, m), 2.12-2.29 (1H, m),2.31 (3H, s), 2.52 (1H, dd, J10.1,15.3 Hz), 2.92 (1H, q, J6.3 Hz), 3.22(3H, s), 3.40-3.55 (1H, m), 4.12 (2H, q, J7.25 Hz), 5.02 (1H, d, J17.5Hz), 5.28 (1H, d, J10.7 Hz), 5.83 (1H, d, J 9.9 Hz), 6.63 (1H, s), 6.78(1H, dd, J10.7,17.5 Hz), and 8.88 (1H, s).

Step 2. Mutilin 14-{N-[(1-ethyl-5-methylpyrazol-3-yl)carbonyl]carbamate}

The product from step 1, (0.130 g) in 1,4-dioxan (3.5 ml) was stirred atroom temperature for 5 h with Lukas reagent (1.0 ml). The solution wasthen diluted with ethyl acetate and neutralized with saturated sodiumhydrogen carbonate solution. The organic solution was washed withsaturated sodium chloride solution, dried (MgSO₄) and evaporated toyield the crude product. After purification by silica gelchromatography, the title compound was isolated as a white solid, (0.133g); ¹ H NMR (CDCl₃) 0.80 (3H, d, J6.5 Hz), 0.90 (3H, d, J7.0 Hz), 1.19(3H, s), 1.35-1.88 (m), 1.46 (3H, t, J7.22 Hz), 1.55 (3H, s), 2.30 (3H,s), 2.05-2.45 (5H, m), 3.38 (1H, dd, J6.5,10.9 Hz), 4.10 (2H, q, J7.25Hz), 5.22 (1H, dd, J1.6,17.4 Hz), 5.39 (1H, dd, J1.4,10.9 Hz), 5.85 (1H,d, J8.5 Hz), 6.59 (1H, dd, J11.0,17.4 Hz) 6.61 (1H, s) and 8.80 (1H, s);MS (EI) m/z 499.

EXAMPLE 160 Mutilin14-{N-[(1,5-Dimethylpyrazol-3-yl)-carbonyl]carbamate}

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[(1,5-dimethylpyrazol-3-yl)carbonyl)carbamate}

1,5-Dimethylpyrazole-3-carboxylic acid was converted to the acidchloride and reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.334 g) asdescribed for Example 157. Following purification by silica gelchromatography the title compound was obtained as a colourless foam(0.450 g); ¹ H NMR (CDCl₃) 0.90 (3H, d, J6.9 Hz), 1.00 (3H, d, J6.4 Hz),1.05-1.65 (m), 1.20 (3H, s), 1.35 (3H, s), 1.70(1H, d, J6.5 Hz), 1.78(1H, d, J2.2 Hz), 1.95-2.10 (2H, m), 2.14-2.28 (1H, m), 2.30 (3H, s),2.51 (1H, dd, J10.1,15.3 Hz), 2.92 (1H, q, J6.3 Hz), 3.22 (3H, s),3.40-3.57 (1H, m), 3.81 (3H, s), 5.0 (1H, d, J17.2 Hz), 5.29 (1H, d,J10.7 Hz), 5.82 (1H, d, J 9.9 Hz), 6.63 (1H, s), 6.78 (1H, dd,J10.7,17.5 Hz), and 8.84 (1H, s).

Step 2. Mutilin 14-{N-[(1,5-dimethylpyrazol-3-yl)carbonyl]carbamate}

The product from step 1, (0.420 g) in 1,4-dioxan (4.0 ml) was stirred atroom temperature for 4 h with Lukas reagent (1.4 ml). The solution wasthen diluted with ethyl acetate and neutralized with saturated sodiumhydrogen carbonate solution. The organic solution was washed withsaturated sodium chloride solution, dried (MgSO₄) and evaporated toyield the crude product. After purification by silica gelchromatography, the title compound was isolated as a white solid, (0.360g); 1H NMR (CDCl₃) 0.80 (3H, d, J6.5 Hz), 0.90 (3H, d, J7.0 Hz), 1.19(3H, s), 1.32-1.88 (m), 1.55 (3H, s), 2.29 (3H, s), 2.05-2.45 (5H, m),3.39 (1H, dd, J6.5,10.9 Hz), 3.80 (3H, s), 5.22 (1H, dd, J1.6,17.4 Hz),5.39 (1H, dd, J1.4,10.9 Hz), 5.82 (1H, d, J8.5 Hz), 6.60 (1H, dd,J11.0,17.4 Hz) 6.62 (1H, s) and 8.79 (1H, s); MS (EI) m/z 485.

EXAMPLE 161 Mutilin 14-[N-(N-Methylnipecotyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(N-methylnipecotyl)carbamate]p (±)-Ethyl N-methylnipecotate (5.0g) was dissolved in 5M hydrochloric acid (100 ml) and stirred at roomtemperature for 16 h. The solution was then evaporated at reducedpressure and the residue re-evaporated from toluene (×2). Triturationgave the hydrochloride salt of (±)-N-methylnipecotic acid as a whitesolid (3.91 g).

The hydrochloride salt of (±)-N-methylnipecotic acid (1.0 g) wassuspended in dichloromethane (25 ml) and stirred at room temperature for2 h with oxalyl chloride (0.58 ml) and DMF (1 drop). The solvent wasthen evaporated to yield the hydrochloride salt of N-methylnipecotylchloride as a pale yellow solid.

The above acid chloride (0.596 g) was suspended in dry dichloromethaneand stirred at room temperature for 4 h with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.334 g), silvercyanate (0.450 g) and triethylamine (0.276 ml). The suspension was thenfiltered through Celite, diluted with ethyl acetate and washed withwater and saturated sodium chloride solution. The organic solution wasdried (MgSO₄), filtered and evaporated to yield the crude product.Silica gel column chromatography, eluting with a gradient of 0-5% 9:1methanol/35% ammonia solution in dichloromethane gave the title compoundas a diastereomeric mixture and as a colourless oil (0.290 g); ¹ H NMR(CDCl₃) 0.85 and 0.88 (2×d, all 3H, J6.9 Hz), 1.00 (3H, d, J6.4 Hz),1.05-1.85 (m), 1.20 (3H, s), 1.25 (3H, s), 1.9-2.40 (6H, m), 2.32 (3H,2×s), 2.48 (1H, m), 2.69 (1H, broad res.), 2.80-2.98 (3H, broad q,),3.22 (3H, s), 3.40-3.53 (1H, m), 4.98 (1H, d, J17.6 Hz), 5.29 (1H, d,J10.7 Hz), 5.62-5.72 (1H, 2×d, J9.9 Hz) and 6.78-6.91 (1H,m); MS (EI)m/z 503.

Step 2. Mutilin 14-[N-(N-Methylnipecotyl)carbamate]

The product from step 1, (0.250 g) in 1,4-dioxan (3.0 ml) was stirred atroom temperature for 4 h with conc. hydrochloric acid (2.0 ml). Thesolution was then diluted with ethyl acetate and neutralized withsaturated sodium hydrogen carbonate solution. The organic solution waswashed with saturated sodium chloride solution, dried (MgSO₄) andevaporated to yield the crude product. After purification by silica gelchromatography, eluting with a gradient of 0-5% 9:1 methanol/35% ammoniasolution in dichloromethane, the title compound was isolated as adiastereoisomeric mixture and as a white foam, (0.205 g); ¹ H NMR(CDCl₃) 0.78 (3H, 2×d, J6.7 Hz), 0.89 (3H, d, J7.0 Hz), 1.19 (3H, s),1.35-2.40 (m), 1.47 (3H, s), 2.30 (3H, 2×s),2.63-2.90 (2H, broad res.),3.35 (1H, broad res.), 5.22 (1H, d, J17.4 Hz), 5.39 (1H, dd, J1.4,11.0Hz), 5.60-5.72 (1H, 2×d, Hz), and 6.63 (1H, dd, J11.0,17.4 Hz); MS (EI)m/z 488.

EXAMPLE 162 Mutilin 14-[N-(1-Methylpyrrolidin-3-oyl)-carbamate}

Step 1. 3-Ethoxycarbonyl-1-methylpyrrolidin-2-one

1-Methyl-2-pyrrolidinone (9.9 g) and diethyl carbonate (50 g) weredissolved in toluene and refluxed for 1 h with the provision for theremoval of water (Dean and Stark apparatus). After cooling, sodiumhydride (50% dispersion in oil; 8.53 g) was carefully added and thestirred suspension was heated to reflux for 4 h under an atmosphere ofargon. After cooling, acetic acid (15 ml) was added and the suspensionwas filtered. The filtrate was evaporated and the residuechromatographed over silics gel to yield the desired product as acolourless oil (5.9 g); ¹ H NMR (CDCl₃) 1.30 (3H, t), 2.18-2.50 (2H, m),2.88 (3H, s), 3.3-3.59 (3H, m), 4.25 (2H, t).

Step 2. 3-Ethoxycarbonyl-1-methylpyrrolidine

The product from step 1 (2.0 g) was dissolved in dry dichloromethane(MDC) and added to a solution of triethyloxonium tetrafluoroborate (2.8g) in MDC (100 ml). The solution was stirred under argon at roomtemperature for 16 h., and then evaporated. The residue was dissolved inethanol, cooled to ice-bath temperature under argon and sodiumborohydride (0.889 g) was added. The resulting solution was stirred atroom temperature for 16 h. Water (15 ml) was added and the solution wasevaporated and re-evaporated from toluene (×2). The residue waschromatographed over silica gel, eluting with a gradient of 0-20%methanol/35% ammonia solution (9:1) in MDC, to yield the desired productas a pale yellow oil (0.450 g); MS (ES) m/z 158 (MH⁺).

Step 3. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-1-methylpyrrolidin-3-oyl)carbamate]

The ethyl ester from step 2 was converted to the acid chloride by theprocedure described in example 5, step 1. This acid chloride was reactedwith (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.668 g)according to the procedure of example 5 to yield the title compound as adiastereomeric mixture and as a pale yellow foam (0.350 g); MS (ES) m/z489 (MH⁺).

Step 4. Mutilin 14-[N-(1-Methylpyrrolidin-3-oyl)carbamate]

The product from step 3, (0.320 g) in 1,4-dioxan (4.0 ml) was stirred atroom temperature for 4 h with conc. hydrochloric acid (2.0 ml). Thesolution was then diluted with ethyl acetate and neutralized withsaturated sodium hydrogen carbonate solution. The organic solution waswashed with saturated sodium chloride solution, dried (MgSO₄) andevaporated to yield the crude product. After purification by silica gelchromatography, eluting with a gradient of 0-5% 9:1 methanol/35% ammoniasolution in dichloromethane, the title compound was isolated as adiastereoisomeric mixture and as a pale yellow foam, (0.245 g); ¹ H NMR(CDCl₃) inter alia 0.75 (3H, d, J6.7 Hz), 0.89 (3H, d, J7.0 Hz), 1.19(3H, s), 1.48 (3H, s), 2.42 (3H, 2×s),2.82-3.05 (2H, broad res.), 3.37(1H, broad res.), 5.22 (1H, d), 5.38 (1H, d) 5.60-5.72 (1H, 2×d, J8.6Hz), and 6.50-6.65 (1H, m); MS (ES) m/z 475 (MH⁺).

EXAMPLE 163 Mutilin 14-[N-(1-Allylpiperidin-4-oyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-allylpiperidin-4-oyl)carbamate]

1-Allylpiperidine-4-carboxylic acid was converted to the acid chloridehydrochloride by the procedure described in Example 161. This acidchloride was then reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.334 g) by theprocedure outlined in Example 161 to yield the title compound as acolourless foam (0.373 g) after silica gel column chromatography; MS(ES) m/z 529 (MH⁺).

Step 2. Mutilin 14-[N-(1-Allylpiperidin-4-oyl)carbamate]

The product from Step 1, (0.340 g) in 1,4-dioxan (3.0 ml) was stirred atroom temperature for 7 h with conc. hydrochloric acid (2.0 ml). Thesolution was then diluted with ethyl acetate and neutralized withsaturated sodium hydrogen carbonate solution. The organic solution waswashed with saturated sodium chloride solution, dried (MgSO₄) andevaporated to yield the crude product. After purification by silica gelchromatography, eluting with a gradient of 0-10% 9:1 methanol/35%ammonia solution in dichloromethane, the title compound was isolated asa white solid, (0.192 g); ¹ H NMR (CDCl₃) 0.75 (3H, d, J6.5 Hz), 0.89(3H, d, J7.0 Hz), 1.20 (3H, s), 1.40-2.45 (m), 1.45 (3H, s), 2.90-3.10(5H, m) 3.39 (1H, dd, J6.6,10.4 Hz), 5.10-5.30 (3H, m), 5.37 (1H, dd,J1.2,10.9 Hz), 5.70 (1H, d, J8.4 Hz), 5.78-5.98 (1H, m), 6.50 (1H, dd,J11.10,17.4 Hz) and 7.43 (1H, s); MS (ES) m/z 515 (MH⁺).

EXAMPLE 164 Mutilin 14-[N-(1-Cyclopropylmethylpiperidin-4-oyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-1-cyclopropylmethylpiperidin-4-oyl)carbamate]

1-Cyclopropylmethylpiperidine-4-carboxylic acid was converted to theacid chloride hydrochloride by the procedure described in Example 161.This acid chloride was then reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (0.334 g) by theprocedure outlined in Example 161 to yield the title compound as acolourless foam (0.450 g) after silica gel column chromatography; MS(EI) m/z 542 (M⁺).

Step 2. Mutilin 14-[N-(1-cyclopropylmethylpiperidin-4-oyl)carbamate]

The product from step 1, (0.400 g) in 1,4-dioxan (5.0 ml) was stirred atroom temperature for 7 h with conc. hydrochloric acid (2.0 ml). Thesolution was then diluted with ethyl acetate and neutralized withsaturated sodium hydrogen carbonate solution. The organic solution waswashed with saturated sodium chloride solution, dried (MgSO₄) andevaporated to yield the crude product. After purification by silica gelchromatography, eluting with a gradient of 0-10% 9:1 methanol/35%ammonia solution in dichloromethane, the title compound was isolated asa white solid, (0.190 g); ¹ H NMR (CDCl₃) 0.12 (2H,m), 0.53 (2H, m),0.75 (3H, d, J6.5 Hz), 0.90 (3H, d, J7.0 Hz), 1.20 (3H, s), 1.35-2.40(m), 142 (3H, s), 2.95-3.18 (3H, m), 3.39 (1H, dd, J6.6,10.4 Hz),5.25(1H, dd, J1.4, 17.4 Hz), 5.38 (1H, dd, J1.2,10.9 Hz), 5.70 (1H, d,J8.4 Hz), 6.50 (1H, dd, J 11.10,17.4 Hz) and 7.40 (1H, s); MS (EI) m/z515.

EXAMPLE 165 Mutilin 14-[N-(nipecotyl)carbamate]

Step 1. N-t-Butoxycarbonyl nipecotic acid

(±)-Nipecotic acid was dissolved in water (25 ml) and stirred rapidly atroom temperature for 16 h with a solution of t-butoxycarbonyl anhydride(3.27 g) in 1,4-dioxan (25 ml). The solution was then evaporated tosmall volume, adjusted to pH 2.0 by the addition of 5M hydrochloric acidsolution, and the resulting precipitate was extracted withdichloromethane. The organic solution was washed with brine, dried(MgSO₄) and evaporated at reduced pressure. The residue was trituratedwith ether/hexane and the resulting white solid collected by filtration(1.10 g); MS (EI) m/z 229.

Step 2. Mutilin11-dichloroacetyl-14-[N-(N-t-butoxycarbonyl-nipecotyl)carbamate]

The product from Step 1 (0.458 g) was converted to the acid chloride bythe procedure described in Example 161. This was then dissolved in drydochloromethane (20 ml) and stirred vigorously at room temperature for 3days with silver cyanate (0.6 g), mutilin 11-dichloroacetate (0.432 g)and tetrakis(triphenylphosphine)palladium(0) (0.002 g). The suspensionwas filtered through Celite and the solvent evaporated at reducedpressure. The residue was chromatographed over silics gel, eluting withethyl acetate/hexane mixtures to provide the title compound as a whitefoam (0.213 g); ν_(max) (CH₂ Cl₂) 3383, 1784, 1755, 1735, 1686 cm⁻¹.

Step 3. Mutilin 14-[N-(N-t-butoxycarbonyl-nipecotyl)carbamate]

The product from Step 2 was dissolved in tetrahydrofuran (2 ml) andstirred vigorously at room temperature for 1.5 h with 1M sodiumhydroxide solution (0.407 ml). The reaction solution was diluted withethyl acetate, washed with brine, dried (MgSO₄) and evaporated. Silicagel column chromatography provided the title compound as adiastereoisomeric mixture and an oil (0.103 g); ν_(max) (CH₂ Cl₂) 3540,3419, 1783, 1732, 1697 cm⁻¹ ; MS (ES) m/z 573 ([M-H]⁻).

Step 4. Mutilin 14-[N-(nipecotyl)carbamate]

The product from Step 3 (0.08 g) was dissolved in dichloromethane (2 ml)and stirred at room temperature for 16 h with trifluoracetic acid (0.120ml). The solvent was then evaporated and the residue was partitionedbetween ethyl acetate and saturated sodium hydrogen carbonate solution.The organic solution was washed with brine, dried (MgSO₄) and evaporatedat reduced pressure. Silica gel column chromatography, eluting with agradient of 0-10% methanol/35% ammonia solution (9:1) in dichloromethaneprovided the title compound as a diastereoisomeric mixture and as awhite foam (0.035 g); ν_(max) (CH₂ Cl₂) 1771, 1734, 1702 cm⁻¹ ; ¹ H NMR(CDCl₃) inter alia 0.78 (3H, 2×d, 6.9 Hz), 0.89 (3H, d, 7.02), 1.20 (3H,2×s,), 1.48 (3H, s), 3.32-3.41 (1H, broad res.), 5.22 (1H, d, J17.3 Hz),5.37 (1H, d, J11.1Hz), and 6.60 (1H, 2×dd, J10.9, 17.3 Hz); MS (CI) m/z475 (MH⁺).

EXAMPLE 166 Mutilin 14-[N-(4-amino-3-methoxybenzoyl)]-carbamate

Step 1. 3-Methoxy-4-Nitrobenzoyl chloride

To a stirred solution of 3-methoxy-4-nitrobenzoic acid (1.21 g, 6.24mmol) in dry dichloro-methane (6 ml) was added oxalyl chloride (1.1 ml)followed by N,N-dimethylformamide (1 drop). The mixture was stirred atroom temperature under argon for 3 hours. The solvent was evaporated invacuo. The residue was purified by chromatography on silica gel elutingwith 50% ethyl acetate in hexane to yield the title compound (0.89 g,66%); ν_(max) (CH₂ Cl₂) 1771 cm⁻¹ ; MS (EI) m/z 215 (M⁺). Found M⁺214.9984, C₈ H₆ NO₄ Cl requires 214.9985.

Step 2.(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin-14-[N-(3-methoxy-4-nitrobenzoyl)]-carbamate

Silver cyanate (669 mg, 4.5 mmol) was suspended in dry dichloromethane(10 ml) under an atmosphere of argon. A solution of the acid chloridefrom Step 1 (0.89 g, 4.1 mmol) in dichloromethane (10 ml) was added andthe heterogeneous mixture stirred at reflux under subdued light. After40 minutes the reaction was allowed to cool and treated with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (668 mg, 2.0 mmol)and the reaction stirred for 17 hours. The mixture was filtered throughcelite. The extract was washed with saturated sodium hydrogen carbonate(×2) and brine, dried (MgSO₄) and the solvent evaporated in vacuo. Theresidue was purified by chromatography on silica gel eluting with 20, 30and 40% ethyl acetate in hexane to yield the title compound (720 mg,65%) ν_(max) (CH₂ Cl₂) 3054, 2987, 1780, 1698 and 1421 cm⁻¹ ; ¹ H NMR(CDCl₃) inter alia 3.23 (3H,s), 3.42-3.52 (1H,m), 4.03 (3H, s), 5.03(1H, d, J 17.4 Hz), 5.31 (1H, d, J 10.7 Hz), 5.86 (1H, d, J 9.9 Hz),6.66 (1H, dd, J 10.7, 17.5 Hz), 7.34 (1H, dd, J 1.6, 8.3 Hz), 7.62 (1H,d, J, 1.6 Hz), 7.89 (1H, d, J 8.3 Hz), 8.07 (1H, bs); MS (CI) m/z 574.3(MNH₄ ⁺).

Step 3.(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin-14-]N-(4-amino-3-methoxybenzoyl)]-carbamate

(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N(3-methoxy-4-nitro-benzoyl)]carbamate (720 mg, 1.29 mmol) wassuspended in ethanol (30 ml). Addition of ethyl acetate (6 ml) withwarming brought about complete dissolution. Tin(II) chloride (1.26 g,6.65 mmol) was added and the reaction warmed to reflux whilst under anatmosphere of argon. After 4 hours the solvent was evaporated in vacuoand the residue taken up in ethyl acetate and water, an emulsion wasformed and removed by filtration through Kieselguhr. The organic phasewas neutralised with sodium hydrogen carbonate (×2), washed with brineand dried (MgSO₄). The residue was purified by chromatography on silicagel eluting with 20, 30, 40 and 60% ethyl acetate in hexane to yield thetitle compound (211 mg, 31%); ν_(max) (CH₂ Cl₂) 3100, 2986, 1771, 1698,1617 and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 3.22 (3H, s), 3.42-3.50(1H, m), 3.91 (3H, s), 4.32 (2H, s), 5.01 (1H, d, J 17.5 Hz), 5.29 (1H,d, J 10.7 Hz), 6.66 (1H, d, J 8.2 Hz), 6.75 (1H, dd, J 10.6, 17.5 Hz),7.20 (1H, dd, J 1.9, 8.2 Hz),7.40 (1H,d, J 1.8 Hz), 7.99 (1H,bs); MS(EI) m/z 526 (M⁺).

Step 4. Mutilin-14-[N-(4-amino-3-methoxybenzoyl)]-carbamate

The product of Step 3 (191 mg, 0.36 mmol) in dioxan (2 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (2 ml) and thereaction stirred at room temperature for 1 hour. The solution was pouredinto ethyl acetate and saturated sodium hydrogen carbonate solution. Theaqueous phase was re-extracted with ethyl acetate (×2) and the combinedorganic phases were washed with brine. The organic phase was dried(MgSO₄) and the solvent evaporated in vacuo. The residue was purified bychromatography on silica gel eluting with 60, 70, 80, 90 and 100% ethylacetate in hexane to yield the title compound 56 mg, 30%); ν_(max) (CH₂Cl₂) 3100, 2986, 1772, 1733, 1617 and 1479 cm⁻¹ ; ¹ H NMR (CDCl₂), interalia 3.34-3.41 (1H, m), 3.90 (3H, s), 4.29 (2H, s), 5.27 (1H, dd J 1.4,17.4 Hz), 5.36 (1H, dd, J1.4, 11.0 Hz), 5.83 (1H, d, J 8.4 Hz), 6.58(2H, dd, J 8.9, 15.3 Hz), 6.65 (1H, d, J 6.2 Hz), 7.17 (1H, dd, J 1.9,8.2 Hz), 7.37 (1H, d, J 1.8 Hz),7.85 (1H,bs); MS (NH₃ DCI) m/z 513(MH⁺).

EXAMPLE 167 Mutilin-14-[N-(4-fluorobenzoyl)]-carbamate

Step 1.(3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin-14-[N-(4-fluorobenzoyl)]-carbamate

4-Fluorobenzoyl chloride (0.57 ml, 4.82 mmol) was reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (978 mg, 2.92 mmol)and silver cyanate (787 mg, 5.25 mmol) in dichloromethane (12 ml), asfor Example 166, Step 2, to afford the title compound (979 mg, 82%);ν_(max) (CH₂ Cl₂) 3420, 3054, 2986, 1778, 1698, 1604 and 1479 cm⁻¹ ; ¹ HNMR (CDCl₃) inter alia 3.23 (3H, s), 3.42-3.50 (1H, m), 5.02 (1H, d, J17.5 Hz), 5.28 (1H, d, J 9.9 Hz), 5.85 (1H, d, 10.0 Hz), 6.70 (1H, dd, J10.7 ,17.5 Hz), 7.14-7.21 (2H, m), 7.84-7.89 (2H, m),8.07 (1H,bs); MS(CI) m/z 517 (MNH₄ ⁺).

Step 2. Mutilin 14-[N-(4-fluorobenzoyl)]-carbamate

The product of Step 1 (959 mg, 1.92 mmol) in dioxane (12 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (12 ml), as forExample 166, Step 4, to afford the title compound (140 mg, 15%); ν_(max)(CH₂ Cl₂) 3414, 3054, 2987, 1779, 1684, 1604, and 1479 cm⁻¹ ; 1H NMR(CDCl₃) inter alia 3.33-3.40 (1H, m), 5.22 (1H, dd, J 1.4,17.4 Hz), 5.33(1H, dd, J 1.4, 10.9 Hz), 5.81 (1H, d, J 8.5 Hz), 6.52 (1H, dd, J 11.0,17.3 Hz), 7.03-7.17 (2H, m), 7.80-7.88 (2H, m), 8.30 (1H, bs); MS(Electrospray) m/z 503 (MNH₄ ⁺).

EXAMPLE 168 Mutilin 14-[N-(4-methylsulphonyl benzoyl)]-carbamate

Step 1. 4-Methylsulphonylbenzoyl chloride

To a stirred solution of 4-methylsulphonyl benzoic acid (1 g, 4.99 mmol)in dry dichloromethane (10 ml) was added oxalyl chloride (0.88 ml, 9.87mmol) followed by N,N-dimethyl formamide (2 drops). The reaction wasstirred at room temperature under argon for 5 hours. The solvent wasevaporated in vacuo. The product was used immediately in the nextreaction; ν_(max) (CH₂ Cl₂) 1784 cm⁻¹.

Step 2. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-methyl-sulphonyl benzoyl]-carbamate

The product from Step 1 in dichloromethane (12 ml) was treated withsilver cyanate (787 mg, 5.25 mmol) and(3R)-3-deoxo-1-deoxy-3-methoxy-11-oxo4-epi-mutilin (814 mg, 2.43 mmol)and the reaction stirred for 2 hours. The title compound was isolated bythe same procedure as described in Example 166, Step 2, (1.19 g, 91%);ν_(max) (CH₂ Cl₂) 3064, 2984, 1780, 1718 and 1476 cm⁻¹ ; ¹ H NMR (CDCl₃)inter alia 3.09 (3H, s), 3.23 (3H, s), 3.42-3.49 (1H, m), 5.03 (1H, d, J17.4 Hz), 5.31 (1H, d, J 10.7 Hz), 5.85 (1H, d, J 9.9 Hz), 6.68 (1H, dd,J 10.7, 17.5 Hz), 7.96-8.00 (2H, m), 8.04-8.07 (2H, m), 8.12 (1H, bs);MS (Electrospray) m/z 558 (M-H⁻).

Step 3. Mutilin 14-[N-(4-methylsulphonyl benzoyl)]-carbamate

The product of Step 2 (1.17 g, 2.14 mmol) in dioxane (13 ml) was treatedwith a saturated solution of zinc chloride in conc. HCl (13 ml), as forExample 166, Step 4, to afford the title compound (342 mg, 30%); ν_(max)(CH₂ Cl₂) 3057, 2936, 1782, 1733 and 1478 cm⁻¹ ; ¹ H NMR (CDCl₃) interalia 3.08 (3H, s), 3.38 (1H, dd, J 10.7, 6.6 Hz), 5.2H (1H, dd, J 17.4,1.4 Hz), 5.38 (1H, dd, J 10.9, 1.3 Hz), 5.82 (1H, d, J 8.5 Hz), 6.53(1H, dd, J 11.1 ,17.4 Hz), 7.94-7.97 (2H, m), 8.02-8.05 (2H, m), 8.07(1H, s); MS (Electrospray) m/z 544 (M-H⁻).

EXAMPLE 169 Mutilin14-[N-(3-(2-Dimethylaminoethoxy)-4-fluorobenzoyl)]-carbamate

Step 1. 4-Fluoro-3-hydroxybenzoic acid

Sulphuric acid (concentrated, 11 ml) was stirred and heated to 90° C.2-Fluoro-5-trifluoro-methylphenol (2.5 g, 13.88 mmol) was added portionwise during 25 minutes. The mixture was heated to 120° C. for 10minutes. The mixture was cooled to ambient temperature and poured onto amixture of ice and water. The precipitate was isolated, washed withwater and dried, to afford the title compound (1.01 g, 47%); ν_(max)(CH₂ Cl₂) 3420, 3054, 2987, 1636 and 1422 cm⁻¹ ; MS (EI) m/z 156 (M⁺).Found M⁺ 156.0223, C₇ H₅ O₃ F requires 156.0223.

Step 2. 3-Acetoxy-4-fluorobenzoic acid

The product from Step 1 (1.0 g, 6.41 mmol) in dichloromethane (35 ml)was treated with triethylamine (1.95 ml, 12.97 mmol) and4-dimethylaminopyridine (24.7 mg, 0.20 mmol). The reaction was cooled inan ice-bath and treated with acetic anhydride (0.62 ml, 6.57 mmol) andstirred for 2 hours at room temperature under argon. The solution waswashed with HCl (5M) and water, dried (MgSO₄) and the solvent evaporatedin vacuo to afford the title compound (1.08 g, 86%); ν_(max) (CH₂ Cl₂)3054, 2987, 1777, 1670 and 1422 cm⁻¹ ; MS (Electrospray) m/z 197 (M-H⁻).Found M⁺ 198.0326, C₉ H₇ O₄ F requires 198.0328.

Step 3. 3-Acetoxy-4-fluorobenzoyl chloride

The product from Step 2 (1.06 g, 5.35 mmol) in dichloromethane (14 ml)was treated with oxalyl chloride (0.60 ml, 6.88 mmol) followed byN,N-dimethylformamide (1 drop), as for Example 168, Step 1. The productwas used immediately in the next reaction ν_(max) (CH₂ Cl₂) 1778 cm⁻¹.

Step 4. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(3-acetoxy-4-fluorobenzoyl]-carbamate

The product from Step 3 in dichloromethane (20 ml) was treated withsilver cyanate (0.84 g, 5.60 mmol) and(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-epi-mutilin (0.64 g, 1.92 mmol)and the reaction stirred for 3 hours. The title compound (70% pure) wasisolated by the same procedure as described in Example 166, Step 2,(1.06 g, 96%); ν_(max) (CH₂ Cl₂) 3418, 3054, 2986, 1779, 1697 and 1422cm⁻¹ ; MS (Electrospray) m/z 556 (M-H⁺).

Step 5. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-fluoro-3-hydroxybenzoyl]-carbamate

The product from Step 4 (1.06 g, 1.90 mmol of 70% pure material) indioxane (15 ml) was treated with 1.0M sodium hydroxide solution (7 ml)for 3 hours at room temperature. The reaction was poured into ethylacetate and dilute HCl. The aqueous phase was re-extracted with ethylacetate. The organic phase was washed with brine, dried (MgSO₄) and thesolvent removed in vacuo. The residue was purified by chromatography onsilica gel eluting with 20, 30, 40 and 50% ethyl acetate in hexane toafford the title compound (420 mg, 43%); ν_(max) (CH₂ Cl₂) 3420, 3054,2986, 1778, 1697, and 1480 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 2.52 (1H,dd, J 10.1, 15.3 Hz), 2.90 (1H, q, J 6.3 Hz), 3.23 (1H, s), 3.42-3.49(1H, m), 5.01 (1H, d, J 17.5 Hz), 5.27 (1H, d, J 10.7 Hz), 5.85 (1H, d,J 9.9 Hz), 6.69 (1H, dd, J 10.7 and 17.5 Hz), 7.14-7.21 (1H, m),7.33-7.39 (1H, m), 7.52-7.56 (1H, m), 8.05 (1H, bs); MS (ES) m/z 516(MH⁺). Found 515.2686 C₂₉ H₃₈ NO₆ F requires 515.2683.

Step 6. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-N-[3-(2-dimethyl-aminoethoxy)-4-fluorobenzoyl]-carbamate

The product from Step 5 (400 mg, 0.78 mmol) was dissolved in acetone (6ml) and treated with dimethylaminoethylchloride hydrochloride (113 mg,0.78 mmol) and potassium carbonate (213 mg). The reaction was heated toreflux for 12 hours under argon. The reaction was diluted with ethylacetate and washed with brine and water. The organic phase was dried(MgSO₄) and the solvent removed in vacuo. The residue was purified bychromatography on silica gel eluting with 25 and 50% ethanol in ethylacetate to afford the title compound (150 mg, 33%); ν_(max) (CH₂ Cl₂)3054, 2986, 1777, 1698 and 1480 cm⁻¹ ; ¹ H NMR (CDCl₃) 2.38 (6H, s),2.55(1H, dd, J 10.1, 15.2 Hz), 2.81 (2H, t, J5.7 Hz), 2.91 (1H, dd, J 6.5,12.9 Hz), 3.23 (3H, s), 3.43-3.50 (1H, m), 4.21 (2H, t, J 5.7 Hz), 5.03(1H, d, J 17.4 Hz), 5.31 (1H, d, J 10.7 Hz), 6.72 (1H, dd, J 10.7 and17.5 Hz), 7.12-7.20 (1H, m), 8.02 (1H, bs).

Step 7. Mutilin14-N-[3-(2-dimethylaminoethoxy)-4-fluorobenzoyl]-carbamate

The product from Step 6 (80 mg, 0.14 mmol) in dioxane (1 ml) was treatedwith conc. HCl (1 ml) and the reaction stirred at room temperature for 4hours. The title compound was isolated by the same procedure asdescribed in Example 166, Step 4, (65mg, 76%); ν_(max).(CH₂ Cl₂) 3054,2988, 1777, 1732, 1609 and 1422 cm⁻¹. ¹ H NMR (CDCl₃) inter alia 2.45(6H, s), 2.91 (2H, t, J 5.5 Hz) 3.37 (1H, d, J 6.4 Hz), 4.28 (2H, t, J5.5 Hz), 5.23 (1H, dd, J 1.3, 17.4 Hz), 5.36 (1H, dd, J 1.3, 11.1 Hz),5.83 (1H, d, J 8.4 Hz), 6.55 (1H, dd, J 11.0, 17.3 Hz), 7.10-7.19 (1H,m), 7.33-7.39 (1H, m), 7.55-7.62 (1H, m), 8.33 (1H, bs); MS (ES) m/z 573(M+H⁺), 571 (M-H⁻).

EXAMPLE 170 Mutilin14-{N-[4-(2-dimethylaminoethyloxy)-benzoyl]}-carbamate hydrochloride

Step 1 (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-{N-[4-(2-dimethyl-aminoethyloxy)benzoyl]}-carbamate

A solution of (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(4-hydroxy-benzoyl)]-carbamate (1 g, 2 mmole) in acetone (20 ml)was treated with powdered K₂ CO₃ (560 mg) and2-dimethylaminoethylchloride hydrochloride (290 mg), and stirred atreflux under argon for 11 hours. The mixture was diluted with EtOAc,washed with water, dried and evaporated. Chromatography on silica,eluting with 2:1 EtOAc/EtOH gave the title compound as a yellow foam(0.51 g, 45%); ν_(max) (CHCl₃) 3436, 1775, 1697, 1606, 1579, 1512, 1488,1168 cm⁻¹ ; ¹ H NMR δ (CDCl₃) 0.87 (3H, d, J 6.7 Hz), 0.98 (3H, d, J 6.3Hz), 1.0-1.6 (12H, m), 1.6-1.75 (2H, m), 1.85-2.05 (2H, m), 2.1-2.2 (1H,m), 2.32 (6H, s), 2.4-2.55 (1H, m), 2.73 (2H, t, J 5.5 Hz), 2.87 (1H, q,J 6.3 Hz), 3.18 (3H, s), 3.35-3.5 (1H, m), 4.08 (2H, t, J 5.5 Hz), 4.95(1H, d, J 17.5 Hz), 5.22 (1H, d, J 10.7 Hz), 5.81 (1H, d, J 9.8 Hz),6.67 (1H, dd, J 17.5 and 10.7 Hz), 6.94 (2H, d, J 8.8 Hz), 7.81 (2H, d,J 8.8 Hz); MS (ammonia CI) m/z 569 (MH⁺, 10%), 352 (20%), 317 (70%), 303(50%), 235 (100%), 209 (70%); (negative ion electrospray) m/z 567 (M-H⁻,100%).

Step 2 Mutilin 14-{N-[4-(2-dimethylaminoethyloxy)-benzoyl]}-carbamate

The product from Step 1 (0.5 g) in dioxan (6 ml) was ice-cooled, treatedwith a saturated solution of ZnCl₂ in conc. HCl (2 ml) and stirred atroom temp. for 5 hours. The mixture was diluted with EtOAc, washed withexcess aqueous NaHCO₃ and water, dried and evaporated. Chromatography onsilica, eluting with 3:1 and then 1:1 EtOAc/EtOH, gave the titlecompound as a gum (230 mg, 47%); ν_(max) (CHCl₃) 3565, 3442, 1777, 1731,1709, 1606, 1579, 1513, 1469 cm⁻¹ ; ¹ H NMR δ(CDCl₃) 0.79 (3H, d, J 6.4Hz), 0.87 (3H, d, J 6.9 Hz), 1.0-1.2 (4H, m), 1.3-1.8 (11H, m), 2.0-2.3(5H, m), 2.36 (6H, s), 2.78 (2H, t, J 5.5 Hz), 3.36 (1H, d, J 6.3 Hz),4.11 (2H, t, J 5.5 Hz), 5.20 (1H, dd, J 17.5 and 1.3 Hz), 5.31 (1H, dd,J 11 and 1.1 Hz), 5.80 (1H, d, J 8.3 Hz), 6.52 (1H, dd, J 17.5 and11Hz), 6.95 (2H, d, J 8.9 Hz), 7.79 (2H, d, J 8.9 Hz), 8.40 (1H, s); MS(EI) m/z 554 (M⁺, 5%), 163 (100%); (NH₃ DCI) m/z 555 (MH⁺, 30%), 235(100%).

Step 3 Mutilin 14-{N-[4-(2-dimethylaminoethyloxy)benzoyl]}-carbamatehydrochloride

The product from Step 2 (225 mg) in EtOAc (5 ml) was treated with 4M HClin dioxan (0.25 ml). The solvents were evaporated to leave the productas a white solid (193 mg). ν_(max) (CHCl₃) 3676, 3434, 2287 (br), 1778,1733, 1654, 1607, 1468 cm⁻¹ ; ¹ H NMR δ((CD₃)₂ SO) 0.70 (3H, d, J 5.9Hz), 0.83 (3H, d, J 7.7 Hz), 1.0-1.2 (4H:, m), 1.2-1.8 (10H, m), 2.0-2.3(4H, m), 2.42 (1H, s), 2.83 (6H, s), 3.4-3.6 (3H, m), 4.43 (2H, t, J 5Hz), 4.55 (1H, d, J 5.9 Hz, disappears on D₂ O exchange), 5.0-5.2 (2H,m), 5.60 (1H, d, J 7.8 Hz), 6.26 (1H, dd, J 17.5 and 11.1 Hz), 7.10 (2H,d, J 8.9 Hz), 7.88 (2H, d, J 8.9 Hz), 10.36 (1H, br s, disappears on D₂O exchange), 10.63 (1H, s, disappears on D₂ O exchange).

EXAMPLE 171 Mutilin 14-{N-[4-(glucosyloxy)-benzoyl]}-carbamate

Step 1. Mutilin14-{N-[4-(tetra-O-acetyl-glucosyloxy)-benzoyl]}-carbamate

A solution of acetobromo-alpha-D-glucose (411 mg, 1 mmol) in acetone (2ml) was added to a solution of mutilin14-[N-(4-hydroxy-benzoyl)]-carbamate(483 mg, 1 mmol) and 1N sodiumhydroxide (1 ml) in water (2 ml) and acetone (5 ml). After three hoursat room temperature a further portion of 1N sodium hydroxide (1 ml) wasadded followed by acetobromo-alpha-D-glucose (411 mg) in acetone (2 ml).The mixture was left overnight at room temperature and then diluted withwater and extracted with ethyl acetate. The extract was washed withbrine, dried (MgSO₄) and evaporated to a foam which was chromatographedon silica gel, using 20% acetone-toluene to give the product as a whitefoam (140 mg): Rf 0.2; ν_(max) (CHCl₃) 3439 w, 1757 br, 1721 (shoulder)cm⁻¹.; ¹ H NMR (d₆ acetone) inter alia 8.6 (1H, br s, NH), 7.80-7.82(2H, arom), 7.02-7.04 (2H, arom), 6.57 (1H, dd, J 17.5, 11), 5.81 (1H,d, J 8, H-14), 5.35 (1H, dd, J 11, 1.5), 5.32 (1H, dd, J 9, 9, glucH-3), 5.28 (1H, dd, J 9,9, gluc H-2), 5.23 (1H, dd, J 17.5, 1.5), 5.21(1H, d, J 7.4, gluc H-1), 5.16 (1H, dd, J 9,9, gluc H-4), 4.28 (1H, ddJ12.3, 5.5, gluc H-6), 4.17 (1H, dd, J12.3, 2.5, gluc H-6), 3.94 (1H,ddd, J 7.9, 5.5, 2.5, gluc H-5), 3.40 (1H, dd, J 10.4, 6.5); ¹³ C NMRinter alia 169.2, 169.4, 170.1 and 170.4 (4×C═O of acetate), 98.2 (CH ofglucoside); MS (+ve ion electrospray) m/z 814 (MH⁺), 831 (MNH₄ ⁺), 836(MNa⁺).

Step 2. Mutilin 14-{N-[4-(glucosyloxy)-benzoyl]}-carbamate

The product of Step 1 (117 mg, 0.14 mmol) was partly dissolved inmethanol (4 ml) and triethylamine (0.02 ml) was added. The mixture wasstirred at room temperature for a total of 48 h during which timefurther portions of triethylamine (0.02 ml×2) were added whilemonitoring the reaction by tlc. The mixture was evaporated to drynessand chromatographed on silica gel, using 20% methanol-chloroform givingthe title compound as a white solid (55 mg, 61%): Rf 0.33; ¹ H NMR (d₆acetone) inter alia 8.00(1H, br s, NH), ca7.9 (2H, arom), ca7.15 (2H,arom), 6.46 (1H, dd, J 17.6, 11), 5.77 (1H, d, J 8, H-14), 5.25 (1H, dd,J 17.6, 2), 5.18 (1H, dd, J 11, 2), 4.60 (1H, d J 3.5, exch D₂ O), 4.35(1H, d, J 3.5, exch D₂ O), 4.27 (1H, d, J3.5 exch D₂ O), 3.87 (1H, dd, J11.8, 1.4 with D₂ O); MS (-ve ion electrospray) m/z 644 (100%, M-H⁻).

EXAMPLE 172 Mutilin 14-[N-(2-azido-phenyl-acetyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(2-azido-phenyl-acetyl)]-carbamate

A solution of (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (667mg, 2 mmol) in dichloromethane (25 ml) was added to a stirred mixture ofD(-)-alpha-azido-phenylacetyl chloride (5 mmol) and silver cyanate (750mgs, 5 mmol) in dichloromethane (10 ml). The mixture was stirredovernight at room temperature, filtered and evaporated to dryness. Thecrude product was chromatographed on silica gel, eluting with 5%acetone-toluene to give the title compound as a white solid (841 mg,80%), Rf 0.32; ν_(max) (CHCl₃) 3389, 2119, 1787, 1756, 1719, 1697 cm⁻¹ ;¹ H NMR (CDCl₃) inter alia 8.0 (1H, br s, exch D₂ O), 7.42 (5H, arom),6.49 (1H, dd, J ca 18, 10.7), 5.70 (1H, d, J 10), 5.52 (1H, brs,PhCH--CO), 5.26 (1H, d, J 10.7); MS (-ve ion electrospray) m/z 535(M-H⁻).

Step 2. Mutilin 14-[N-(2-azido-phenyl-acetyl)]-carbamate

The product of Step 1 (536 mg, 1 mmol) was dissolved in dioxan (15 ml)and a saturated solution of zinc chloride in conc hydrochloric acid (4ml) was added with cooling in bath of cold water. The clear yellowsolution was stirred at room temperature for 3.5 hour. The mixture wasdiluted with cold aq. sodium bicarbonate and extracted with ethylacetate. The extract was washed with water and with brine and dried(MgSO₄). Evaporation gave a crude product which was purified bychromatography on silica gel eluting with 5% acetone-toluene giving thetitle compound as a white foam (413 mg, 79%); Rf 0.05; ν_(max) (CHCl₃)3565, 3388, 2112, 1789, 1756 (shoulder), 1725 cm⁻¹ ;¹ H NMR (CDCl₃)inter alia 7.84 (1H, br s), 7.40 (5H, arom), 6.38 (1H, dd, J 17, 11),5.67 (1H, d, J 8.5), 5.54 (1H, br s, PhCH--CO), 5.23 (1H, d, J 11), 5.11(1H, d, J 17); 3.33 (1H, dd, J 10.5, 6.5); MS (+ve ion electrospray) m/z540 (MNH₄ ⁺), MS (-ve ion electrospray) m/z 521 (100%, M-H⁻).

EXAMPLE 173 19,20-Dihydro-mutilin14-[N-(alpha-amino-phenylacetyl)]-carbamate hydrochloride

Mutilin 14-[N-(2-azido-phenyl-acetyl)]-carbamate (240 mg, 0.46 mmol)(Example 172) was dissolved in dioxan (5 ml) and water (1 ml) and 4M HClin dioxan (0.25 ml) was added. The solution was shaken with 10% Pd--C(100 mg) in an atmosphere of hydrogen for 45 minutes. The catalyst wasremoved by filtration and washed with aqueous dioxan. The filtrate wasevaporated to an oil and azeotroped with ethanol and with chloroform.The resulting crude solid was recrystallised from ethanol-ether to givethe title compound as an off-white solid (123 mg, 50%), mp 175-180° C.;ν_(max) (CHCl₃) ca 2600-3200, 1757, 1733, 1703 cm¹⁻ ; ¹ H NMR (d₄methanol) inter alia 7.49 (5H, arom), 5.72 (1H, br, PhCH--CO), 5.55 (1H,d, J 8), 3.41(1H, d, J 6); ¹³ C NMR (CDCl₃ -d₄ methanol) inter alia 7.7,10.9, 14.5, 16.0, 20.4, 24.7, 26.0, 26.7, 30.2, 34.4 (CH and CH₂), 36.5,40.5, 40.7, 41.9, 45.5, 57.0, 58.4, 71.5, 75.9, 128.5, 129.2, 130.0,131.4, 150.5, 169, 218.0; MS (NH₃ DCI) m/z 499 (100%, MH⁺); MS(glycerolFAB) Found m/z 499.3170 (MH⁺) C₂₉ H₄₃ N₂ O₅ requires 499.3172.

EXAMPLE 174 Mutilin 14-[N-(cyclohexyl-acetyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(cyclohexyl-acetyl)]-carbamate

A solution cyclohexyl-acetyl isocyanate (2.5 mmol) in dichloromethane(10 ml) was added to one of(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (334 mg, 1 mmol) indichloromethane (3 ml) at room temperature. The solution was stirredovernight at room temperature and evaporated to dryness. The crudeproduct was chromatographed on silica gel, eluting with ethyl acetate1:2 to give the title compound as a white foam (252 mg, 50%), Rf 0.42;ν_(max) (CHCl₃) 3395, 1782w, 1749, 1697 cm⁻¹.; ¹ H NMR (CDCl₃) interalia 7.47 (1H, br s, exch D₂ O), 6.64 (1H, dd, J 17.5, 10.5), 5.74 (1H,d, J 10), 5.33 (1H, d, J 10.5), 5.03 (1H, d, J 17.5), 3.4-3.5 (1H, m);MS (NH3 DCI) ) m/z 519 (8%, MNH₄ ⁺).

Step 2. Mutilin 14-[N-(cyclohexyl-acetyl)]-carbamate

The product of Step 1 (400 mg, 0.8 mmol) was dissolved in dioxan (4 ml)and a saturated solution of zinc chloride in conc hydrochloric acid (2ml) was added. The solution was stirred at room temperature for 2 hourand then diluted with cold aq. sodium bicarbonate and extracted withethyl acetate. The extract was washed with aq. sodium bicarbonate andwith brine and dried (MgSO₄). Evaporation gave a crude product which waspurified by chromatography on silica gel eluting with ethyl acetate 1:2giving the title compound as a white solid (152 mg, 39%); mp 198-200°C.; ν_(max) (CHCl₃) 3397, 2928, 1735, 1712 cm⁻¹ ; ¹ H NMR (CDCl₃) interalia 7.29 (1H, br s), 6.49 (1H, dd, J 17.3, 11), 5.70 (1H, d, J 7.5),5.38 (1H, dd, J 11, 1.4), 5.23 (1H, d, J 17.3, 1.4); 3.36 (1H, dd, J10.5, 6.5), 2.62 (2H, d, J6.6); MS (-ve ion electrospray) m/z 486 (50%,M-H⁻).

EXAMPLE 175 Mutilin 14-[N-(cinnamoyl)]-carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(cinnamoyl)]-carbamate

A solution cinnamoyl isocyanate (2 mmol) in dichloromethane (5 ml) wasadded to one of (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin(501 mg, 1.5 mmol) in dichloromethane (5 ml) at room temperature. Thesolution was stirred for 1 hour and a further portion of cinnamoylisocyanate (1 mmol) in dichloromethane (2.5 ml) was added. The mixturewas stirred at room temperature for 2 days and evaporated to dryness.The crude product was chromatographed on silica gel, eluting with ethylacaetate 1:4 to give the title compound as a white solid (710 mg, 93%),Rf 0.38; ν_(max) (CHCl₃) 3400, 1776w, 1747, 1690, 1621 cm⁻¹.; ¹ H NMR(CDCl₃) inter alia 7.89 (1H, d, J 16), 7.59-7.65 (2H, m), 7.58 (1H, d, J16), 7.50 (1H, br s, exch D₂ O), 7.4-7.5 (3H, m), 6.68 (1H, dd, J 17.5,10.5), 5.78 (1H, d, J 10), 5.36 (1H, d, J 10.5), 5.05 (1H, d, J 17.5),3.4-3.5 (1H, m), 3.23 (3H, s); MS (NH₃ DCI) ) m/z 508 (MH⁺), 525 (MNH₄⁺).

Step 2. Mutilin 14-[N-(cinnamoyl)]-carbamate

The product of Step 1 (507 mg, 1 mmol) was dissolved in dioxan (4 ml)and a saturated solution of zinc chloride in conc hydrochloric acid (2ml) was added. The solution was stirred at room temperature overnightand then diluted with cold aq. sodium bicarbonate and extracted withethyl acetate. The extract was washed with water and with brine anddried (MgSO₄). Evaporation gave a crude product which was purified bychromatography on silica gel eluting with ethyl acetate 1:2 giving thetitle compound as a white solid (316 mg, 64%); mp 148-151° C.; ν_(max)(CHCl₃) 3400, 1735, 1682, 1622 cm⁻¹ ; MS (NH₃ DCI)) m/z 494 (10%, MH⁺),511 (12%, MNH₄ ⁺).

EXAMPLE 176 19,20-Dihydro-mutilin 14-(1-Methylpiperidin-4-oyl)-carbamate

Mutilin 14-(1-methylpiperidin-4-oyl)-carbamate (100 mg) as a solution inTHF (5 ml) with 10% palladium/carbon catalyst was hydrogenated for 1hour at room temperature. The catalyst was filtered off through celiteand the solution concentrated to give the title compound as a colourlesssolid, (100 mg, quant.); ν_(max) (CH₂ Cl₂) 3630(w), 3390(w), 1732, 17101470 and 1406 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 1.40 (3H, s), 1.43 (3H,s), 2.89 (2H, d J 11.4 Hz), 3.07 (1H, m), 3.41 (1H, d, J 6.0 Hz), 5.55(1H, d, J 8.03 Hz) and 7.38 (1H, s); MS(EI) m/z 490 (M⁺) (Found: M⁺,490.341; C₂₈ H₄₆ N₂ O₅ requires 490.341).

EXAMPLE 177 19,20-Dihydro-mutilin 14-(1-Methylpiperidin-4-oyl)-carbamatehydrochloride

19,20-Dihydro-mutilin 14-(1-methylpiperidin-4-oyl)-carbamate (348 mg) inethyl acetate at room temperature was vigorously stirred and treatedwith 1M hydrochloric acid in ether in a dropwise fashion until nofurther precipitation was observed. The title compound was filtered offand dried in vacuo over 12 hours, and was thus obtained as a white solid(302 mg, 81%); ¹ H NMR (D₂ O) inter alia 0.68 (6H, m), 0.86 (3H, d, J7.2 Hz), 2.85 (3H,s), 3.04 (2H, d, J 11.0), 3.55 (3H, m) and 5.56 (1H, dJ 7.8 Hz).

EXAMPLE 178 19,20-Dihydromutilin14-{N-[(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylcarbonyl]}-carbamate

A solution of mutilin14-{N-[(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylcarbonyl]}-carbamate (95 mg,0.20 mmol) in 1:1 ethanol:tetrahydrofuran (10 ml) was hydrogenated for12 hours over 10% palladium on carbon (90 mg). The solution was filteredthrough celite and the solvent evaporated in vacuo to yield the titlecompound (85 mg, 87%); ν_(max) (KBr) 3421, 2957, 1772, 1733, 1702 and1464 cm⁻¹ ; ¹ H NMR (d₆ -DMSO) inter alia 0.68 (3H, d, J 71 Hz), 0.82(3H, d, J 6.8 Hz), 4.46 (1H, d, J 5.9 Hz), 5.46 (1H, d, J 7.6 Hz), 10 53(1H, bs); MS (EI) m/z 488 (M⁺). Found: M⁺, 488.3256; C₂₈ H₄₄ N₂ O₅requires 488.3250.

EXAMPLE 179 19,20-Dihydromutilin14-[N-(quinuclidine-4-carbonyl)]-carbamate

A solution of mutilin 14-[N-(quinuclidine-4-carbonyl)]-carbamate (100mg, 0.20 mmol) in 2:1 tetrahydrofuran:ethanol (30 ml) was hydrogenatedfor 1 hour over 10% palladium on carbon (10 mg). The solution wasfiltered through celite and the solvent evaporated in vacuo to yield thetitle compound as a white solid (90 mg, 90%); ν_(max) (CH₂ Cl₂) 2960,1782, 1733, 1716 and 1479 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 0.69 (3H, d,J 6.6 Hz), 3.42 (1H, d, J 5.9 Hz), 5.61 (1H, d, J 8.2 Hz), 7.37 (1H,bs); MS (EI) m/z 502 (M⁺). Found: M⁺, 502.3411; C₂₉ H₄₆ N₂ O₅ requires502.3407.

EXAMPLE 180 19,20-Dihydro-mutilin14-[N-(3-(2-Dimethylaminoethoxy)-4-fluorobenzoyl)]-carbamate

Mutilin 14-[N-(3-(2-dimethylaminoethoxy)-4-fluorobenzoyl)]-carbamate(0.200 g) was dissolved in ethanol (30 ml) and shaken at ambienttemperature and atmospheric pressure with hydrogen in the presence of10% palladium on charcoal catalyst for 2 hours. The suspension wasfiltered through Celite and the filtrate evaporated to yield the titlecompound as a white foam (0.201 g); ¹ H NMR inter alia (CDCl₃) 0.75-0.85(6H, m), 0.90-1.05 (6H, m), 1.51 (3H, s), 2.38 (6H, s), 2.79 (2H, t, J5.61 Hz), 3.41 (1H, d, J 5.95 Hz), 4.20 (2H, t, J 5.64 Hz), 5.70 (1H, d,J 8.03 Hz), 7.11 (1H, dd, J 8.43 and 10.35 Hz), 7.28-7.38 (1H, m), 7.55(1H, dd, J 2.0 and 7.9 Hz), 8.0 (1h, broad s); MS (ES) m/z 575 (MH⁺).

EXAMPLE 181 Mutilin 14-[N-(Quinuclidin-3-oyl)carbamate]

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(quinuclidin-3-oyl)carbamate]

Quinuclidine-3-carboxylic acid was converted to the acid chloridehydrochloride by the procedure described in Example 161. This acidchloride was then reacted with(3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (1.002 g) by theprocedure outlined in Example 161 to yield the title compound as acolourless foam (1.116 g) after silica gel column chromatography; MS(ES) m/z 515 (MH⁺).

Step 2. Mutilin 14-[N-(Quinuclidin-3-oyl)carbamate]

The product from Step 1, (1.13 g) in 1,4-dioxan (12 ml) was stirred atroom temperature for 7 h with conc. hydrochloric acid (5 ml). Thesolution was then diluted with ethyl acetate and neutralized withsaturated sodium hydrogen carbonate solution. The organic solution waswashed with saturated sodium chloride solution, dried (MgSO₄) andevaporated to yield the crude product. After purification by silica gelchromatography, eluting with a gradient of 0-20% 9:1 methanol/35%ammonia solution in dichloromethane, the title compound was isolated asa white solid, (0.340 g). This solid, which was a mixture of twodiastereoisomers, was digested in hot ethyl acteate and the resultingwhite solid was collected by filtration to yield one purediastereoisomer of the title compound (0.140 g); ¹ H NMR inter alia(CDCl₃) 0.75 (3H, d, J6.5 Hz), 0.90 (3H, d, J7.0 Hz), 1.20 (3H, s), 1.40(3H, s), 2.70-3.10 (5H, m), 3.20-3.42 (3H, m), 5.15-5.40 (2H, ddd), 5.70(1H, d, J8.3Hz), 6.50 (1H, dd, J10.95, 17.4Hz) and 7.40 (1H, s); MS (ES)m/z 501 (MH⁺). The mother liquors contained predominantly the otherdiastereoisomer of the title compound (0.200 g); ¹ H NMR inter alia(CDCl₃) 0.75 (3H, d, J6.5 Hz), 0.90 (3H, d, J7.0 Hz), 1.20 (3H, s), 1.41(3H, s), 2.12-2.4 (3H, m), 2.70-3.10 (5H, m), 3.24-3.42 (3H, m),5.15-5.45 (2H, m), 5.69 (1H, d, J8.3 Hz), 6.50 (1H, dd, J11.0, 17.35 Hz)and 7.40 (1H, s); MS (ES) m/z 501 (MH⁺).

EXAMPLE 182 Mutilin14-{N-[(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylcarbonyl]}-carbamatehydrochloride

A solution of mutilin14-{N-[(3S,4R)-1-azabicyclo[2.2.1]hept-3-ylcarbonyl]}-carbamate (1.0 g;2.06 mmol) in acetone (100 ml) was treated with 1M HCl in diethyl ether(4.2 ml; 4.20 mmol). The solution was stirred for 1 hour at roomtemperature and then concentrated in vacuo. The residue was trituratedwith diethyl ether to yield the title compound as a white solid (1.02 g,95%); ν_(max) (KBr) 3421, 2924, 1772, 1734, 1704 and 1465 cm⁻¹ ; ¹ H NMR(D₂ O) inter alia 0.62 (3H, d, J 6.0 Hz), 0.90 (3H, d, J 6.9 Hz), 5.22(2H, dd, J 16.7, 11.1 Hz), 5.61 (1H, d, J 8.1 Hz), 6.35 (1H, dd, J 17.5,11.1 Hz).

EXAMPLE 183 Mutilin 14-[N-(1-azabicyclo[3.2.1]octan-5-oyl)]carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-azabicyclo[3.2.1]octan-5-oyl)]-carbamate

Triethylamine (0.58 ml, 4.2 mmol) was added to a stirred mixture ofracemic 1-azabicyclo[3.2.1]octane-5-carbonyl chloride hydrochloride (4mmol), (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (668 mg, 2mmol) and silver cyanate (600 mg) in dichloromethane (25 ml). Themixture was stirred overnight at room temperature, filtered and thefiltrate evaporated to dryness. The crude product was purified bychromatography on silica gel, eluting with 35% ammoniasolution:methanol:dichloromethane 1:9:90 to give the title compound as awhite solid (480 mg), Rf 0.1; ¹ H NMR (CDCl₃) inter alia 7.4 (1H, br s),5.79 (1H, d, J 10), 3.21 (3H, s), 2.75-3.0 (6H, m); MS (+ve ionelectrospray) m/z 515 (30%, MNH₄ ⁺), m/z 556 (100%, M+H+MeCN⁺).

Step 2. Mutilin 14-[N-(1-azabicyclo[3.2.1]octan-5-oyl)]-carbamate

The product of Step 1 (480 mg, 0.93 mmol) was dissolved in dioxan (2.5ml) and conc hydrochloric acid (2.5 ml) was added slowly with cooling inan ice bath. The clear solution was stirred at room temperature for 4hours and then diluted with water and basified by addition of sodiumcarbonate. The mixture was extracted with ethyl acetate and washed withbrine. Drying (MgSO₄) and evaporation gave a crude product which waspurified by chromatography on silica gel eluting with 35% ammoniasolution:methanol:dichloromethane 1:9:90, giving two diastereoisomers ofthe title compound as a white solid (274 mg, 58%); Rf 0.08; ν_(max)(CHCl₃) 2962, 1772, 1736m, 1628 cm⁻¹ ; ¹ H NMR (CDCl₃) inter alia 7.58(1H, br s), 6.51 (1H, dd, J 17, 11), 5.75 (1H, d, J 8.4), 5.34 (1H, dd,J 11, 1.25), 5.19 (1H, d, J 17, 1.25), 3.36 (1H, br), 3.08-3.2 (1H,m),2.7-3.05 (5H, m); MS (+ve ion electrospray) m/z 501 (100%, MH⁺), MS (-veion electrospray) m/z 499 (100%, M-H⁻).

EXAMPLE 184 Mutilin 14-[N-(1-azabicyclo[2.2.2]octan-2-oyl)]carbamate

Step 1. (3R)-3-Deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin14-[N-(1-azabicyclo[2.2.2]octan-2-oyl)]-carbamate

Triethylamine (0.2 ml, 1.5 mmol) was added to a stirred mixture ofracemic 1-azabicyclo[2.2.2]octane-2-carbonyl chloride hydrochloride (ca3 mmol), (3R)-3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epi-mutilin (501 mg,1.5 mmol) and silver cyanate (225 mg) in dichloromethane (10 ml). Themixture was stirred overnight at room temperature, filtered and thefiltrate diluted with dichloromethane and washed with aq sodiumbicarbonate and with brine. Drying (MgSO₄) and evaporation gave a crudeproduct which was purified by chromatography on silica gel, eluting withethyl acetate: n-hexane 1:1. The title compound was obtained as acolourless gum (220 mg), Rf 0.12.

Step 2. Mutilin 14-[N-(1-azabicyclo[2.2.2]octan-2-oyl)]-carbamate

The product of Step 1 (200 mg) was dissolved in dioxan (2 ml) and conchydrochloric acid (2 ml) was added slowly with cooling in an ice bath.The clear solution was stirred at room temperature for 3 hours and thendiluted with water and basified by addition of sodium bicarbonate. Themixture was extracted with ethyl acetate and washed with brine. Drying(MgSO₄) and evaporation gave a crude product which was purified bychromatography on silica gel eluting with 5% methanol in chloroform,giving two diastereoisomers of the title compound as a white foam (135mg, 69%); Rf 0.08; ν_(max) (CHCl₃) 3309, 2946, 1780, 1735m, 1713 cm⁻¹ ;MS (+ve ion electrospray) m/z 501 (22%, MH⁺), MS (-ve ion electrospray)m/z 499 (100%, M-H⁻).

We claim:
 1. A compound of formula (1A) or a pharmaceutically acceptablesalt or derivative thereof ##STR5## in which Y is a carbamoyloxy group,in which the N-atom is unsubstituted, or mono- or di-substituted.
 2. Acompound of general formula (3), or a pharmaceutically acceptable saltor derivative thereof ##STR6## in which: R¹ is vinyl or ethyl;R² and R³are the same or different groups selected from hydrogen;a straight orbranch chained, saturated or unsaturated, optionally substituted, C₁ toC₆ hydrocarbon group; a saturated or unsaturated, optionallysubstituted, C₃ to C₈ cyclic hydrocarbon group; an optionallysubstituted heterocyclic group; an optionally substituted aryl group; ortogether form an optionally substituted cyclic group of 3 to 8 ringatoms, optionally containing one additional heteroatom selected from N,O and S, and optionally fused to a hydrocarbon ring, a heterocyclicgroup or an aromatic group; orR² is one of the above monovalent groupsand R³ is a group selected from SO₂ R⁴, COR⁵, OR⁵ and NR⁶ R⁷ where R⁴ isselected from a straight or branch chained, saturated or unsaturated,optionally substituted, C₁ to C₆ hydrocarbon group; a saturated orunsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;an optionally substituted heterocyclic group; an optionally substitutedaryl group; an optionally substituted C₁ to C₆ alkylamino group; and anoptionally substituted arylamino group; R⁵ is selected from hydrogen; astraight or branch chained, saturated or unsaturated, optionallysubstituted, C₁ to C₆ hydrocarbon group; a saturated or unsaturated,optionally substituted, C₃ to C₈ cyclic hydrocarbon group; an optionallysubstituted heterocyclic group; and an optionally substituted arylgroup; R⁶ and R⁷ are the same or different groups selected fromhydrogen; a straight or branch chained, saturated or unsaturated,optionally substituted, C₁ to C₆ hydrocarbon group; a saturated orunsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;an optionally substituted heterocyclic group, and an optionallysubstituted aryl group; or together form an optionally substitutedcyclic group of 3 to 8 ring atoms, optionally containing one additionalheteroatom selected from N, O and S, and optionally fused to ahydrocarbon ring, a heterocyclic group or an aromatic group.
 3. Acompound according to claim 2 being mutilin 14-(N-phenylcarbamate).
 4. Amethod for preparing a compound of claim 1 which comprises reacting acompound of formula (4) where X is hydrogen or a hydroxyl protectinggroup, or a compound of formula (5) with an appropriately substitutedcarbamate-forming reagent ##STR7##
 5. A process for the preparation of acompound according to claim 2, which comprises reacting a compound offormula (4) in which X is hydrogen or a hydroxyl protecting group, with(a) a compound R² NCO,(b) a compound R² R³ NCOCl, or (c) phosgene or achloroformate or a carbonate followed by a compound R² R³ NH,where R²and R³ are the same or different groups selected from hydrogen; astraight or branch chained, saturated or unsaturated, optionallysubstituted, C₁ to C₆ hydrocarbon group; a saturated or unsaturated,optionally substituted, C₃ to C₈ cyclic hydrocarbon group; an optionallysubstituted heterocyclic group; an optionally substituted aryl group; ortogether form an optionally substituted cyclic group of 3 to 8 ringatoms, optionally containing one additional heteroatom selected from N,O and S, and optionally fused to a hydrocarbon ring. a heterocyclicgroup or an aromatic group; orR² is one of the above monovalent groupsand R³ is a group selected from SO₂ R⁴, COR⁵, OR⁵ and NR⁶ R⁷ where R⁴ isselected from a straight or branch chained, saturated or unsaturated,optionally substituted, C₁ to C₆ hydrocarbon group; a saturated orunsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;an optionally substituted heterocyclic group; an optionally substitutedaryl group; an optionally substituted C₁ to C₆ alkylamino group; and anoptionally substituted arylamino group; R⁵ is selected from hydrogen; astraight or branch chained, saturated or unsaturated, optionallysubstituted, C₁ to C₆ hydrocarbon group; a saturated or unsaturated,optionally substituted, C₃ to C₈ cyclic hydrocarbon group; an optionallysubstituted heterocyclic group; and an optionally substituted arylgroup; R⁶ and R⁷ are the same or different groups selected fromhydrogen; a straight or branch chained, saturated or unsaturated,optionally substituted, C₁ to C₆ hydrocarbon group; a saturated orunsaturated, optionally substituted, C₃ to C₈ cyclic hydrocarbon group;an optionally substituted heterocyclic group, and an optionallysubstituted aryl group; or together form an optionally substitutedcyclic group of 3 to 8 ring atoms, optionally containing one additionalheteroatom selected from N, O and S, and optionally fused to ahydrocarbon ring, a heterocyclic group or an aromatic group;and areprotected where appropriate, and where necessary deprotecting the groupX to generate a hydroxyl group at position 11, deprotecting a protectedgroup R² or R³ , converting one group R² or R³ to another group R² orR³, or hydrogenating the vinyl group at position 12 to form an ethylgroup.
 6. A process for the preparation of a compound according to claim2, which comprises reacting a compound of formula (5) with(a) a compoundR² NCO, (b) a compound R² R³ NCOCl, or (c) phosgene or a chloroformateor a carbonate followed by a compound R² R³ NH,where R² and R³ are thesame or different groups selected from hydrogen; a straight or branchchained, saturated or unsaturated, optionally substituted, C₁ to C₆hydrocarbon group; a saturated or unsaturated, optionally substituted,C₃ to C₈ cyclic hydrocarbon group; an optionally substitutedheterocyclic group; an optionally substituted aryl group; or togetherform an optionally substituted cyclic group of 3 to 8 ring atoms,optionally containing one additional heteroatom selected from N, O andS, and optionally fused to a hydrocarbon ring, a heterocyclic group oran aromatic group; orR² is one of the above monovalent groups and R³ isa group selected from SO₂ R⁴, COR⁵, OR⁵ and NR⁶ R⁷ where R⁴ is selectedfrom a straight or branch chained, saturated or unsaturated, optionallysubstituted, C₁ to C₆ hydrocarbon group; a saturated or unsaturated,optionally substituted, C₃ to C₈ cyclic hydrocarbon group; an optionallysubstituted heterocyclic group; an optionally substituted aryl group; anoptionally substituted C₁ to C₆ alkylamino group; and an optionallysubstituted arylamino R⁵ is selected from hydrogen; a straight or branchchained, saturated or unsaturated, optionally substituted, C₁ to C₆hydrocarbon group; a saturated or unsaturated, optionally substituted,C₃ to C₈ cyclic hydrocarbon group; an optionally substitutedheterocyclic group; and an optionally substituted aryl group; R⁶ and R⁷are the same or different groups selected from hydrogen; a straight orbranch chained, saturated or unsaturated, optionally substituted, C₁ toC₆ hydrocarbon group; a saturated or unsaturated, optionallysubstituted, C₃ to C₈ cyclic hydrocarbon group; an optionallysubstituted heterocyclic group, and an optionally substituted arylgroup; or together form an optionally substituted cyclic group of 3 to 8ring atoms, optionally containing one additional heteroatom selectedfrom N, O and S, and optionally fused to a hydrocarbon ring, aheterocyclic group or an aromatic group;and are protected whereappropriate, treating the product with an acid, deprotecting a protectedgroup R² or R³, converting one group R² or R³ to another group R² or R³,or hydrogenating the vinyl group at position 12 to form an ethyl group.7. A pharmaceutical composition comprising a compound according to claim1, 2 or 3, together with a pharmaceutically acceptable carrier orexcipient.
 8. A method of treating microbial infections in humanscomprising administering an antimicrobially effective amount of acompound according to claim 1, 2 or 3, or a pharmaceutical compositioncomprising a compound according to claim 1, 2 or 3, together with apharmaceutically acceptable carrier or excipient, to a patient in needthereof.
 9. A method comprising the step of using a compound accordingto claim 1, 2 or 3, in the preparation of a medicament composition foruse in the treatment of microbial infections.
 10. A method of treatingmicrobial infections in domesticated mammals comprising administering anantimicrobially effective amount of a compound according to claim 1, 2or 3, or a pharmaceutical composition comprising a compound according toclaim 1, 2 or 3, together with a pharmaceutically acceptable carrier orexcipient, to a patient in need thereof.